My Weekly Reading Progress Report

Signaling at G-protein-coupled serotonin receptors: recent advances and future research directions: Trends in Pharmacological Sciences

www.cell.com

354

onal van der Waals interaction with the N-H of the indole nucleu
Thr3.37 likely acts as a hydrogen bond acceptor, whereas the adjacent residue, Ala5.46, may be forming an addit
This suggests that this residue likely is involved in recognition of the amine portion of the ligand and that the N-alkyl substitution of ligands can differentially be recognized dependent on the type of residue present.
Cys in all other 5-HT receptors,
Thr i
erved Asp3.32

Structure and Function of Serotonin G protein Coupled Receptors

6 annotations

www.ncbi.nlm.nih.gov

648

. Serotonergic signaling has also been implicated in bronchoconstriction (Hershenson et al. 1995) and the control of rhythmic breathing (Manzke et al. 2010).
Serotonergic dysregulation has been linked to numerous psychological conditions, particularly major depressive disorder
and memory
Within the CNS, 5-HT is involved in the regulation of mood and social cognition (Jenkins et al. 2016), neurogenesis
The serotonin transporter (SERT) is responsible for the reuptake of free 5-HT in the synaptic cleft; this is, in fact, the mechanism of action exploited by selective serotonin reuptake inhibitors (SSRIs), typically used as antidepressants or anxiolytic therapy.
auto- or paracrine factor, and synthesized by both gut neurons and enterochromaffin cells located in the gastrointestinal system
Serotonin acts as a neurotransmitter within the central nervous system (CNS), where it is synthesized by raphe neurons in the brain stem
5-HT receptors are able to exert their influence on several biochemical pathways that are much further downstream
Barring the 5-HT3 receptor, which functions as a ligand-gated ion channel (LGIC) (Reeves and Lummis 2002), all other serotonergic receptors mediate their actions via G proteins.
5-Hydroxytryptamine (5-HT), or serotonin, is most commonly known for its role in the pathophysiology of various neuropsychiatric disorders
We identified 90 molecules in serotonin-serotonin receptor pathway.
Fourteen structurally and functionally distinct receptor subtypes have been identified for serotonin, each of which mediates the neurotransmitter’s effects through a range of downstream signaling molecules and effectors

The 5-Hydroxytryptamine signaling map: an overview of serotonin-serotonin receptor mediated signaling network

12 annotations

www.ncbi.nlm.nih.gov

397

When the platelets bind to a clot, they release serotonin, where it can serve as a vasoconstrictor or a vasodilator while regulating hemostasis and blood clotting.
Serotonin secreted from the enterochromaffin cells eventually finds its way out of tissues into the blood. There, it is actively taken up by blood platelets, which store it.
The serotonin is secreted luminally and basolaterally, which leads to increased serotonin uptake by circulating platelets and activation after stimulation, which gives increased stimulation of myenteric neurons and gastrointestinal motility.[15]

Serotonin - Wikipedia

3 annotations

en.wikipedia.org

374

classical paradigm, in which serotonin works by noncovalent interactions with membrane-bound receptors, and creates many new questions about whether serotonin can exert biological activity by covalently attaching to cellular proteins in other organ systems, including the brain.Go to:
activation of a subset of platelet
serotonin is covalently cross-linked to a variety of adhesion proteins and clotting factors on the platelet cell surface (
activates G protein–dependent signaling pathways and stimulates platelet aggregation
y also play a role in platelet activation through covalent linkage to small G proteins via tissue transglutaminase
SSRIs may actually reduce MIs is intriguing and still awaits prospective testing (26).
SSRI treatment may decrease myocardial infarction (MI) risk. Several case-control studies have observed lower MI rates among depressed patients taking SSRIs versus controls
platelets from serotonin transporter knockout mice, show decreased aggregation responses (22).
Selective serotonin reuptake inhibitors (SSRIs) can increase bleeding time by inhibiting the uptake and storage of platelet serotonin, so caution should be used in patients at high risk for bleeding or on anticoagulants.
erotonin is then secreted by the platelet dense granules during platelet activation and plays a role in promoting platelet aggregation and vasoconstriction of surrounding blood vessels, facilitating hemostasis.
Platelets have significant vesicular serotonin stores but lack the enzymes to synthesize serotonin (21); instead, they take up serotonin from the plasma via the serotonin transporter. S
Serotonin causes vasoconstriction or vasodilation in different vascular beds depending on the particular receptors that are expressed in each vessel wall and surrounding smooth muscle tissue (19). Indeed, activation of 5-HT1B receptors on cerebral blood vessels causes vasodilation, which may partly explain the analgesic effects of the triptan antimigraine drugs (
. This principle explains why drugs targeting a specific serotonin receptor nonetheless have effects on multiple behavioral processes (
anxiety-like behavior is regulated primarily by 5-HT1A and 5-HT2C receptors, among others (14, 15), but the 5-HT2C receptor regulates not only anxiety but also reward processing, locomotion, appetite, and energy balanc
each behavior is regulated by multiple serotonin receptors, each serotonin receptor is expressed in multiple brain regions and likely contributes to the modulation of multiple behavioral processes.

The Expanded Biology of Serotonin

15 annotations

www.ncbi.nlm.nih.gov

326

the active form of vitamin B6.
cofactor pyridoxal phosphate,
This chemical reaction is a result of activity of the enzyme aromatic L-amino acid decarboxylase, or AADC.
converts 5-HTP into 5-HT through a decarboxylation process.
TPH1 and TPH2, of which TPH2 is found exclusively in neurons.
dietary tryptophan is converted into 5-hydroxy-L-tryptophan, or 5-HTP. This is accomplished by the activity of the enzyme tryptophan hydroxylase, or TPH.
chicken, and turkey.
especially egg whites, cheeses, and meats such as pork,
the brain can affect such complex behaviors as reward, motivation, learning, cognition, and anxiety. Serotonin is best known to function in regulation of mood.
. Serotonin levels in the brain can affect such complex behaviors as reward, motivation, learning, cognition, and anxiety.

How is serotonin synthesized in the body? — Brain Stuff

10 annotations

brainstuff.org

365

as a neurotransmitter and neuromodulator and has been implicated in numerous psychiatric conditions and psychological processes.
y 1% of dietary tryptophan is used for serotonin synthesis in the brain
tryptophan is used for serotonin synthesis throughout the body
It is estimated that 95% of mammalian serotonin is found within the gastrointestinal tra

L-Tryptophan: Basic Metabolic Functions, Behavioral Research and Therapeutic Indications

4 annotations

www.ncbi.nlm.nih.gov

360

n indole ring

Tryptophan Biochemistry: Structural, Nutritional, Metabolic, and Medical Aspects in Humans

1 annotation

www.hindawi.com

402

subsequent decarboxylation involving the enzyme l-aromatic acid decarboxylase to serotonin (5-hydroxytryptamine, 5-HT).
Once in the CNS, l-tryptophan is hydroxylated to 5-hydroxytryptophan by the enzyme tryptophan hydroxylase type 2, the rate limiting step in brain serotonin synthesis
Tryptophan is a substrate for the large neutral amino-acid transporter system and competes for transport with several other amino acids essential for brain function
tryptophan first needs to gain access to the central nervous system (CNS) via the blood-brain barrier.

Influence of Tryptophan and Serotonin on Mood and Cognition with a Possible Role of the Gut-Brain Axis

4 annotations

www.ncbi.nlm.nih.gov

531

se antidepressants generally work by increasing serotonin in the brain, 5-HTP could combine with these medications to cause high concentrations of serotonin
Dietary supplements containing 5-HTP are claimed to help promote feelings of happiness and general well-being as well as a wide range of other positives such as appetite control, reduced anxiety, and improved mood, sleep and feelings of relaxation

5-HTP Safety Concerns

2 annotations

www.poison.org

422

SSRIs are also used to treat symptoms of anxiety, panic disorder, and obsessive-compulsive disorders
In 2015, however, other scientists found that mice that lacked serotonin were more susceptible to social stressors than healthy control mi
SSRIs increase serotonin levels by preventing serotonin neurotransmitters from being reabsorbed. Serotonin levels remain high in the brain. This is believed to elevate mood.

Serotonin: Facts, uses, SSRIs, and sources

3 annotations

www.medicalnewstoday.com

385

31, 41, 353, 355, and 357 in the S‐protein‐binding site of ACE2 varied by less than 0.4 Å between the inhibitor‐bound and ‐unbound structures
The S1 domain mediates receptor association, whereas the S2 domain is membrane‐associated and likely undergoes structural rearrangements that mediate membrane fusion

Receptor and viral determinants of SARS‐coronavirus adaptation to human ACE2 | The EMBO Journal

2 annotations

www.embopress.org

600

of 17 residues of the RBD are in contact with 20 residues of ACE2
A total of nine cysteine residues are found in the RBD, eight of which form four pairs of disulfide bonds that are
esidues Ser19–Asp615 of the ACE2 N-terminal peptidase domain, one zinc ion, four N-acetyl-β-glucosaminide (NAG) glycans linked to ACE2 Asn90, Asn322 and Asn546 and to RBD Asn343,
Thr333–Gly526 of the SARS-CoV-2 RB
Specifically, we expressed the SARS-CoV-2 RBD (residues Arg319–Phe541) (Fig. 1a, b) and the N-terminal peptidase domain of ACE2 (residues Ser19–Asp615) in Hi5 insect cells and purified them by Ni-NTA affinity purification and gel filtration
Serial dilutions of the SARS-CoV RBD and SARS-CoV-2 RBD were flowed through with a concentration ranging from 62.5 to 1.9 nM. The resulting data were fit to a 1:1 binding model using Biacore Evaluation Software
Final Ramachandran statistics: 96.44% favoured, 3.56% allowed and 0.00% outliers for the final structure.
structure was determined using the molecular replacement method with PHASER in the CCP4 suit
the RBD is the important region for receptor binding, antibodies that target the conserved epitopes in the RBD will also present a great potential for developing highly potent cross-reactive therapeutic agents against diverse coronavirus species, including SARS-CoV-2.
16 residue changes in the SARS-CoV-2 RBD among 25 epitope positions of
By mapping these epitope residues onto the sequence of SARS-CoV RBD aligned with the sequence of SARS-CoV-2 RBD
where exactly the epitope of CR3022 on the RBDs of SARS-CoV or SARS-CoV-2 is located.
the equilibrium dissociation constant
may have important roles in the binding of
reside in the Asn90-
e involvement of multiple
tyrosine residues that form hydrogen-bonding interaction
K417 and V404 positions of SARS-CoV-2
charged patch on the SARS-CoV-2 RBD
Lys417 t
Outside the RBM, there is a unique ACE2-interacting residue (Lys417) in SARS-CoV-2, which forms salt-bridge interactions with Asp30 of ACE2
At the Gln493/Asn479 position, Gln493 of SARS-CoV-2 interacts with Lys31, His34 and Glu35 of ACE2 and forms a hydrogen bond with Glu35; Asn479 of SARS-CoV interacts with only His34 of ACE2 (
At the Phe486/Leu472 position, Phe486 of SARS-CoV-2 interacts with Gln24, Leu79, Met82 and Tyr83 of ACE2
at which Gln498 of SARS-CoV-2 and Tyr484 of SARS-CoV both interact with Asp38, Tyr41, Gln42, Leu45 and Lys353 of ACE2
Gln498/Tyr484 location
, 8 have the identical residues between the two RBDs, inc
structure-guided sequence alignment and mapped them to their respective sequen
To compare the ACE2-interacting residues on the SARS-CoV-2 and SARS-CoV RBD
, 17 residues are shared between both interactions and most of the contacting residues are located at the N-terminal helix
N-terminal helix of ACE2 by the outer surface
binding site between them
f ACE2 has two lobes
forming the peptide substrate
), which help to stabilize the β sheet structure (Fig. 1c); the remaining pair (Cys480–Cys488) connects the loops in the distal end of the RBM
, three are in the core
crystallography.
d the structure of the SARS-CoV-2 RBD–ACE2 complex using X-ray
Previous cryo-electron microscopy studies of the SARS-CoV spike protein and its interaction with the cell receptor ACE2 have shown that receptor binding induces the dissociation of the S1 with ACE2, prompting the S2 to transit from a metastable pre-fusion to a more-stable post-fusion state that is essential for membrane fusion

Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor | Nature

38 annotations

www.nature.com

675

Cleavage of the S2’ site by host cell proteases is required for successful infection by SARS-CoV
hydrophobic fusion peptide and two heptad repeat regions.

Cryo-EM structure of the SARS coronavirus spike glycoprotein in complex with its host cell receptor ACE2

2 annotations

journals.plos.org

649

Abolishes interaction with SARS-CoV spike glycoprotein

ACE2 - Angiotensin-converting enzyme 2 precursor - Homo sapiens (Human) - ACE2 gene & protein

1 annotation

www.uniprot.org

543

in SARS-CoV-2, slight modification of some residues could improve the interaction with the human cellular receptor: L455, F486, Q493, and N501. In SARS-CoV, two main residues (479 and 487) have been associated to the recognition of the human ACE2 receptor

Role of changes in SARS-CoV-2 spike protein in the interaction with the human ACE2 receptor: An in silico analysis

1 annotation

www.ncbi.nlm.nih.gov

567

The binding affinity of SARS-CoV-2 with ACE2 seems stronger than SARS-CoV, with alterations in several amino acid residues allowing for enhanced hydrophobic interactions and salt bridge formations,

Angiotensin-Converting Enzyme 2: SARS-CoV-2 Receptor and Regulator of the Renin-Angiotensin System

1 annotation

www.ncbi.nlm.nih.gov

600

Disulfide bonds in the SARS-CoV-2 RBD are shown as sticks and indicated by arrows.
SB domain open,
tructure of the SARS-CoV-2 trimeric S protein in its prefusion configuration with 1 of the 3 S1 RBDs in the receptor-accessible up-conformation
y showed a cryo-election microscopy
ACE2 is a type I transmembrane glycoprotein with a single zinc metalloprotease active site that acts as a monocarboxypeptidase cleaving a single amino acid, always phenylalanine.
When the S1 subunit binds to the host cell receptor, it dissociates from the S2 subunit, and the S2 subunit transforms into a stable, postfusion, dumbbell-shaped conformation.4,15 The dumbbell S2 has a bundle structure of 6 helices that inserts into the target host membrane and brings the viral and host membranes together.4
Coronavirus spikes function as class I membrane fusion proteins.

Interaction of SARS-CoV-2 and Other Coronavirus With ACE (Angiotensin-Converting Enzyme)-2 as Their Main Receptor

7 annotations

www.ncbi.nlm.nih.gov

635

r Lys353 in binding other than stabilizing the internal configuration of ACE2 by forming an ion pair with Asp38.
simulations show that Asn501 makes a second hydrogen bond to the main-chain oxygen of Gly352 of ACE2
as long as they are hydrophobic in nature, would not ma
nonspecific, hydrophobic aggregation is key to initiate contact between ACE2 and RBD
no specific side-chain contacts from the receptor ACE2, except the methyl group of Thr27.
crystal structures and from MD simulation
Asp30 to Glu30 in the receptor could also effectively accommodate ion-pair interactions
an ion pair across the otherwise hydrophobic interface in the central region of the binary complex
Val404s-to-Lys417 mutation
crystal and cryo-EM structures and amino acid sequences provided important insights
double mutation of both Lys439s and Asp480s, as in the RBD of SARS-CoV-2, to Leu452 and Ser494, respectively, may not necessarily yield a net destabilizing contribution to binding.
counterbalance the stabilizing effect of ion pairing
Asp480s also forms a tight salt bridge with Lys439s, which is only 3.6 Å from Arg162.
. Indeed, single-site mutation of either Asp480sAla or Asp480sGly abolishes binding activity of 80R for the RBD of SARS-CoV
light and heavy chains
stabilizing since it disrupts an internal salt bridge of 80R (Arg156–Asp202), and Asp202 is only 4 Å away from Glu484.
along with a new ion pair between Glu484 and Arg156(H) thanks to the Pro470s→Glu484 mutation.
crystal structure [Protein Data Bank (PDB)
, Asp355 itself is involved in an internal (among residues of ACE2) salt bridge with Arg357 as well as a hydrogen bond from Tyr41 of the receptor,
Asp355 on the β-sheet/turn of ACE2 receives a hydrogen bond from Thr500 at the tip of the binding loop
Gly502–Lys353 pair is preserved in the SARS-CoV complex, but the other hydrogen bond is absent as a result of the amino acid variation of Thr487s
Asn501 and the backbone of Gly502 each donates a hydrogen bond to the main-chain oxygen atoms of Gly352 and Lys353, respectively.
anchoring the RBD in a groove formed between the turn of an antiparallel β-sheet and the long N-terminal helix of ACE2.
extensive hydrogen-bonding network
does not form specific contacts with ACE2 except remote interactions with the Lys31–Asp35 salt bridge on the N-terminal helix.
ACE2
” Lys31, of
Gln493(Asn479s), which has been recognized as a key residue whose mutation may be associated with the possible civet (from Arg or Lys)-to-human transmission,
demonstrating its significant role in ACE2 binding.
Val→Lys displacement enhances RBD binding to ACE2
in the RBD–ACE2 complex between SARS-CoV-2 and SARS-CoV is the Val404s-to-Lys417 transition at the apex of the interfacial arch, resulting in an ion pair with Asp30 in the 2019 novel coronavirus.
significant role to anchor the dimer interface in the RBD–ACE2 complexes.
hydrophobic contacts
although these two sets of hydrophobic residues are quite different in the two RBDs, they form the same type of physical interactions in both complex structures.
, from Tyr442s, Leu443s, F460s, and Pro462s
other four hydrophobic residues have been mutated in SARS-CoV-2,
Tyr489 is retained from the SARS-CoV sequence,
including Leu455, Phe456, Tyr473, Ala475, and Tyr489, ending with the methyl group of Thr27 of ACE2 tucked in the pocket of the last four residues
The interfacial interactions in the central region across the N-terminal helix of ACE2 are dominated by hydrophobic contacts both within the RBM of SARS-CoV-2 itself and across the interface with the recepto
It is interesting to note that the Leu472s→Phe mutation has been identified previously in a set of five amino acid variations of the original
esidue Leu472s in SARS-CoV is, however, found to point outward, rather than seating in the pocket in the dynamic trajectories, also observed in crystallograph
Tyr83 also donates a hydrogen bond to Asn487
N-terminal end of ACE2 is the hydrophobic contact of Phe486, situated in a pocket fenced by Leu79, Met82, and Tyr83 of ACE2.
The interface between ACE2 and RBD may be roughly divided into hydrophobic and hydrogen-bonding halves.
e three key binding contact regions
etween SARS-CoV-2 and S
structural origin that governs RBD–ACE2 binding and affinity difference between SARS-CoV-2 and SARS-CoV,
Hydrophobic Contacts Play a Central Role in Anchoring RBD to Its Receptor.
uncertainties in side-chain conformation found in different crystal structures (Gln498 and Asn501) and residues in the central region of RBM, including Lys417 and Tyr453
e MD simulations, which are as representative as any other structures of the trajectory, with the four crystal and cryogenic electron microscopy (cryo-EM) structures of SAR2-CoV-2 that have been solved
. Consistent with electrostatic potential complementarity and structural details (discussed below), the observed conformation shift may be attributed to the formation of a salt bridge between Asp30 of ACE2 and Lys417 across the binding groove, along with strengthened loop-anchoring interactions at the bases of the binding interface.
receptor binding motif
RBD is structurally divided into a core region, consisting of five antiparallel strands of β-sheet, which is relatively conserved (87.4% sequence identity), and a more variable
A key mutation from a hydrophobic residue in the SARS-CoV sequence to Lys417 in SARS-CoV-2 creates a salt bridge across the central hydrophobic contact region, which along with polar residue mutations results in greater electrostatic complementarity than that of the SARS-CoV complex.

Enhanced receptor binding of SARS-CoV-2 through networks of hydrogen-bonding and hydrophobic interactions | PNAS

54 annotations

www.pnas.org

573

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} div#help a { text-decoration: none; } div#help span.glyphicon-new-window { font-size: 10px; margin-left: 10px; } Help Sequence of7A97 | SARS-CoV-2 Spike Glycoprotein with 2 ACE2 Bound1: Spike glycoprotein2: Angiotensin-converting enzyme 2ABC MGILPSPGMP ALLSLVSLLS VLLMGCVAET GMFVFLVLLP LVSSQCVNLT20 TRTQLPPAYT30 NSFTRGVYYP40 DKVFRSSVLH50 STQDLFLPFF60 SNVTWFHAIH70 VSGTNGTKRF80 DNPVLPFNDG90 VYFASTEKSN100 IIRGWIFGTT110 LDSKTQSLLI120 VNNATNVVIK130 VCEFQFCNDP140 FLGVYYHKNN150 KSWMESEFRV160 YSSANNCTFE170 YVSQPFLMDL180 EGKQGNFKNL190 REFVFKNIDG200 YFKIYSKHTP210 INLVRDLPQG220 FSALEPLVDL230 PIGINITRFQ240 TLLALHRSYL250 TPGDSSSGWT260 AGAAAYYVGY270 LQPRTFLLKY280 NENGTITDAV290 DCALDPLSET300 KCTLKSFTVE310 KGIYQTSNFR320 VQPTESIVRF330 PNITNLCPFG340 EVFNATRFAS350 VYAWNRKRIS360 NCVADYSVLY370 NSASFSTFKC380 YGVSPTKLND390 LCFTNVYADS400 FVIRGDEVRQ410 IAPGQTGKIA420 DYNYKLPDDF430 TGCVIAWNSN440 NLDSKVGGNY450 NYLYRLFRKS460 NLKPFERDIS470 TEIYQAGSTP480 CNGVEGFNCY490 FPLQSYGFQP500 TNGVGYQPYR510 VVVLSFELLH520 APATVCGPKK530 STNLVKNKCV540 NFNFNGLTGT550 GVLTESNKKF560 LPFQQFGRDI570 ADTTDAVRDP580 QTLEILDITP590 CSFGGVSVIT600 PGTNTSNQVA610 VLYQDVNCTE VPVAIHADQL TPTWRVYSTG SNVFQTRAGC650 LIGAEHVNNS660 YECDIPIGAG670 ICASYQTQTN SPRRARSVAS690 QSIIAYTMSL700 GAENSVAYSN710 NSIAIPTNFT720 ISVTTEILPV730 SMTKTSVDCT740 MYICGDSTEC750 SNLLLQYGSF760 CTQLNRALTG770 IAVEQDKNTQ780 EVFAQVKQIY790 KTPPIKDFGG800 FNFSQILPDP810 SKPSKRSFIE820 DLLFNKVTLA DAGFIKQYGD CLGDIAARDL ICAQKFNGLT860 VLPPLLTDEM870 IAQYTSALLA880 GTITSGWTFG890 AGAALQIPFA900 MQMAYRFNGI910 GVTQNVLYEN920 QKLIANQFNS930 AIGKIQDSLS940 STASALGKLQ950 DVVNQNAQAL960 NTLVKQLSSN970 FGAISSVLND980 ILSRLDPPEA990 EVQIDRLITG1000 RLQSLQTYVT1010 QQLIRAAEIR1020 ASANLAATKM1030 SECVLGQSKR1040 VDFCGKGYHL1050 MSFPQSAPHG1060 VVFLHVTYVP1070 AQEKNFTTAP1080 AICHDGKAHF1090 PREGVFVSNG1100 THWFVTQRNF1110 YEPQIITTDN1120 TFVSGNCDVV1130 IGIVNNTVYD1140 PLQPELDSFK EELDKYFKNH TSPDVDLGDI SGINASVVNI QKEIDRLNEV AKNLNESLID LQELGKYEQS GRENLYFQGG GGSGYIPEAP RDGQAYVRKD GEWVLLSTFL GHHHHHHStructure7A97 | SARS-CoV-2 Spike Glycoprotein with 2 ACE2 BoundTypeAssemblyAsm Id1: Author And Software Defined AssemblyNothing FocusedMeasurementsComponents7A97PresetAddPolymerCartoonDensityAssembly Symmetry// handle viewer select function selectViewer() { var val = $("#viewers").val() console.log('val=' + val + ', pdbid=' + pdbid + ', bionumber=' + bionumber + ', viewerType=' + viewerType) if (val === 'molstar') { window.location.href = '/3d-view/' + pdbid } else if (val === 'ngl') { window.location.href = '/3d-view/ngl/' + pdbid } else if (val === 'jsmol') { window.location.href = '/3d-view/jsmol/' + pdbid } } Select a different viewerMol* (Javascript)NGL (WebGL)JSmol (JavaScript)CitationImages created using Mol* should cite the PDB ID, the corresponding structure publication, Mol* (D. 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Velankar (2018) Mol*: Towards a common library and tools for web molecular graphics MolVA/EuroVis Proceedings. doi:10.2312/molva.20181103), and RCSB PDB.var viewer = new rcsbMolstar.Viewer('viewer'); if (preset === 'validationReport') { viewer.loadPdbId(pdbid, { kind: 'validation', assemblyId: bionumber }); } else if (preset === 'ligandInteraction') { viewer.loadPdbId(pdbid, { kind: 'feature', assemblyId: bionumber, target: { label_comp_id: sele } }); } else if (preset === 'oligoInteraction') { viewer.loadPdbId(pdbid, { kind: 'feature', assemblyId: bionumber, target: { label_asym_id: sele } }); } else if (preset === 'electronDensityMaps') { viewer.loadPdbId(pdbid, { kind: 'density', assemblyId: bionumber }); } else if (preset === 'symmetry') { viewer.loadPdbId(pdbid, { kind: 'symmetry', assemblyId: bionumber, symmetryIndex: parseInt(sele) }); } else { viewer.loadPdbId(pdbid, { kind: 'standard', assemblyId: bionumber }); }AboutAbout UsCiting UsPublicationsTeamCareersUsage & PrivacyHelpContact UsHelp TopicsWebsite FAQGlossaryRCSB PartnersNucleic Acid DatabasewwPDB PartnersRCSB PDBPDBePDBjBMRBRCSB PDB (citation) is hosted byRCSB PDB is a member of theRCSB PDB is funded by the National Science Foundation (DBI-1832184), the US Department of Energy (DE-SC0019749), and the National Cancer Institute, National Institute of Allergy and Infectious Diseases, and National Institute of General Medical Sciences of the National Institutes of Health under grant R01GM133198.

RCSB PDB - 7A97: SARS-CoV-2 Spike Glycoprotein with 2 ACE2 Bound

2 annotations

www.rcsb.org

559

high affinity between the S protein and ACE2 increases the infectivity of SARS-CoV-2.
The SARS-CoV-2 S protein binds to the host cell receptor and induces virus–cell membrane fusion, which plays a vital role in the process of virus invasion.
It is a trimeric class I TM glycoprotein responsible for viral entry,
The S protein on the surface of the virus is a key factor involved in infe
activate the S protein by cleaving it into S1 and S2 subunits
In the S1 subunit, there is an N-terminal domain (14–305 residues) and a receptor-binding domain (RBD, 319–541 residues);
extensive structural rearrangement of the S protein occurs, allowing the virus to fuse with the host cell membrane.
consists of an extracellular N-terminus, a transmembrane (TM) domain anchored in the viral membrane, and a short intracellular C-terminal segment [11].
β coronavirus family.
while the S2 subunit mediates viral cell membrane fusion by forming a six-helical bundle via the two-heptad repeat domain.

Structural and functional properties of SARS-CoV-2 spike protein: potential antivirus drug development for COVID-19 | Acta Pharmacologica Sinica

10 annotations

www.nature.com

517

portion of ACE2 that includes the first α-helix and lysine 353 and proximal residues of the N terminus of β-sheet 5 interacts with high affinity to the receptor binding domain of the SARS-CoV S glycoprotein
ar tissue
ACE2 is a membrane-associated aminopeptidase expressed in vascular endothelia, renal and cardiovascular tissue, and epithelia of the small intestine
National

ACE2 Receptor Expression and Severe Acute Respiratory Syndrome Coronavirus Infection Depend on Differentiation of Human Airway Epithelia

4 annotations

www.ncbi.nlm.nih.gov

480

cleaved from the cell surface by other peptidases, modulating its activity.
It is a type I transmembrane protein with a large catalytic extracellular domain which acts as both a peptidase and a viral receptor.
resides on the cell surface of the epithelial, and sometimes endothelial, cells of the heart, kidney, testes, lung and gastrointestinal tract

The Cell Biology of the SARS Coronavirus Receptor, Angiotensin-Converting Enzyme 2

3 annotations

www.ncbi.nlm.nih.gov

508

decreasing the levels of ACE2, in cells, might help in fighting the infection.
It has also been shown that disruption of S-protein glycosylation significantly impairs viral entry, indicating the importance of glycan-protein interactions in the process.[33]
, the binding of the spike S1 protein of SARS-CoV and SARS-CoV-2 to the enzymatic domain of ACE2 on the surface of cells results in endocytosis and translocation of both the virus and the enzyme into endosomes located within cells

Angiotensin-converting enzyme 2 - Wikipedia

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he angiotensin-converting enzyme 2 (ACE2), previously identified as the cellular receptor for SARS-CoV, also acts as a receptor of the new coronavirus (SARS-CoV-2)
CoV entry into host cells is mediated by its transmembrane spike (S) glycoprotein that forms homotrimers protruding from the viral surface
severe acute respiratory syndrome (SARS)-CoV-2, was found to share similarities with the SARS-CoV that was responsible for the SARS pandemic that occurred in 2002.
In December 2019, a novel coronavirus (CoV) was determined to be responsible for an outbreak of potentially fatal atypical pneumonia, ultimately defined as coronavirus disease-19 (COVID-19), in Wuhan, China

Molecular interaction and inhibition of SARS-CoV-2 binding to the ACE2 receptor | Nature Communications

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S1 binds to a specific cell surface receptor via its receptor-binding domain (RBD), and S2 fuses the host cell and viral membranes, enabling the entry of viral genomes into host cells.
receptor-binding unit S1 and a membrane-fusion unit S2.
The amino acid sequence of spike glycoprotein consists of a large ectodomain, a single-pass transmembrane anchor, and a short C-terminal intracellular tail
The entry of all coronaviruses into host cells is mediated by spike glycoprotein that gives coronaviruses a crown-like appearance by forming spikes on their surface

Structure analysis of the receptor binding of 2019-nCoV - ScienceDirect

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ACE2 - Angiotensin-converting enzyme 2 precursor - Homo sapiens (Human) - ACE2 gene & protein

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The ten structures describe ACE2 binding events which destabilise the spike trimer, progressively opening up, and out, the individual S1 components. The opening process reduces S1 contacts and un-shields the trimeric S2 core, priming fusion activation and dissociation of ACE2-bound S1 monomers
The structures also reveal refolding of an S1 subdomain following ACE2 binding, that disrupts interactions with S2, notably involving Asp61413-15, leading to destabilisation of the structure of S2 proximal to the secondary (S2') cleavage site.

Receptor binding and priming of the spike protein of SARS-CoV-2 for membrane fusion - PubMed

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The spike glycoprotein of the new coronavirus 2019-nCoV contains a furin-like cleavage site absent in CoV of the same clade - ScienceDirect

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spike glycoprotein sars-cov-2 - Google Search

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Viral entry and cell infection trigger the host’s immune response, and the inflammatory cascade is initiated by antigen-presenting cells (APC)
the complex is proteolytically processed by type 2 transmembrane protease TMPRSS2 leading to cleavage of ACE-2 and activation of the spike protein
e SARS spike protein binds to the ACE-2 receptor
Binding of the SARS-CoV to the angiotensin-converting enzyme 2 (ACE-2) receptors in the type II pneumocytes in the lungs triggers a cascade of inflammation in the lower respiratory tract

SARS-CoV-2 and Coronavirus Disease 2019: What We Know So Far

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The virus reaches the lungs after entry in the nose or mouth.
SARS-CoV-2 virus binds to ACE2, it prevents ACE2 from performing its normal function to regulate ANG II signaling. Thus, ACE2 action is "inhibited
, ANG II can increase inflammation and the death of cel
ACE2 is a vital element in a biochemical pathway that is critical to regulating processes such as blood pressure, wound healing and inflammation, called the renin-angiotensin-aldosterone system (RAAS) pathway
Using the spike-like protein on its surface, the SARS-CoV-2 virus binds to ACE2—like a key being inserted into a lock—prior to entry and infection of cells
lungs, heart, blood vessels, kidneys, liver and gastrointestinal tract.

What is the ACE2 receptor, and how is it connected to coronavirus?

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ACE2 is a specific functional receptor for SARS-CoV
The SARS-CoV-2 spike glycoprotein, which binds to ACE2, is a potential target for developing specific drugs, antibodies, and vaccines.

Role of angiotensin-converting enzyme 2 (ACE2) in COVID-19 | Critical Care | Full Text

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