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- PDB-6vkv: Co-crystal structure of GS-6207 bound to HIV-1 capsid hexamer -

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Basic information

Entry
Database: PDB / ID: 6vkv
TitleCo-crystal structure of GS-6207 bound to HIV-1 capsid hexamer
ComponentsCapsid protein p24
KeywordsVIRAL PROTEIN
Function / homology
Function and homology information


viral budding via host ESCRT complex / viral process / ISG15 antiviral mechanism / host multivesicular body / viral nucleocapsid / host cell cytoplasm / host cell nucleus / structural molecule activity / host cell plasma membrane / virion membrane ...viral budding via host ESCRT complex / viral process / ISG15 antiviral mechanism / host multivesicular body / viral nucleocapsid / host cell cytoplasm / host cell nucleus / structural molecule activity / host cell plasma membrane / virion membrane / RNA binding / zinc ion binding / membrane / cytoplasm
Similarity search - Function
Gag protein p6 / Gag protein p6 / gag protein p24 N-terminal domain / Immunodeficiency lentiviral matrix, N-terminal / gag gene protein p17 (matrix protein) / Retroviral nucleocapsid Gag protein p24, C-terminal domain / Gag protein p24 C-terminal domain / Matrix protein, lentiviral and alpha-retroviral, N-terminal / Retrovirus capsid, C-terminal / Retroviral matrix protein ...Gag protein p6 / Gag protein p6 / gag protein p24 N-terminal domain / Immunodeficiency lentiviral matrix, N-terminal / gag gene protein p17 (matrix protein) / Retroviral nucleocapsid Gag protein p24, C-terminal domain / Gag protein p24 C-terminal domain / Matrix protein, lentiviral and alpha-retroviral, N-terminal / Retrovirus capsid, C-terminal / Retroviral matrix protein / Retrovirus capsid, N-terminal / zinc finger / Zinc knuckle / Zinc finger, CCHC-type superfamily / Zinc finger, CCHC-type / Zinc finger CCHC-type profile.
Similarity search - Domain/homology
IODIDE ION / Chem-QNG / Gag polyprotein / Gag polyprotein
Similarity search - Component
Biological speciesHuman immunodeficiency virus 1
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.22 Å
AuthorsBester, S.M. / Kvaratskhelia, M.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID) United States
CitationJournal: Science / Year: 2020
Title: Structural and mechanistic bases for a potent HIV-1 capsid inhibitor.
Authors: Stephanie M Bester / Guochao Wei / Haiyan Zhao / Daniel Adu-Ampratwum / Naseer Iqbal / Valentine V Courouble / Ashwanth C Francis / Arun S Annamalai / Parmit K Singh / Nikoloz Shkriabai / ...Authors: Stephanie M Bester / Guochao Wei / Haiyan Zhao / Daniel Adu-Ampratwum / Naseer Iqbal / Valentine V Courouble / Ashwanth C Francis / Arun S Annamalai / Parmit K Singh / Nikoloz Shkriabai / Peter Van Blerkom / James Morrison / Eric M Poeschla / Alan N Engelman / Gregory B Melikyan / Patrick R Griffin / James R Fuchs / Francisco J Asturias / Mamuka Kvaratskhelia /
Abstract: The potent HIV-1 capsid inhibitor GS-6207 is an investigational principal component of long-acting antiretroviral therapy. We found that GS-6207 inhibits HIV-1 by stabilizing and thereby preventing ...The potent HIV-1 capsid inhibitor GS-6207 is an investigational principal component of long-acting antiretroviral therapy. We found that GS-6207 inhibits HIV-1 by stabilizing and thereby preventing functional disassembly of the capsid shell in infected cells. X-ray crystallography, cryo-electron microscopy, and hydrogen-deuterium exchange experiments revealed that GS-6207 tightly binds two adjoining capsid subunits and promotes distal intra- and inter-hexamer interactions that stabilize the curved capsid lattice. In addition, GS-6207 interferes with capsid binding to the cellular HIV-1 cofactors Nup153 and CPSF6 that mediate viral nuclear import and direct integration into gene-rich regions of chromatin. These findings elucidate structural insights into the multimodal, potent antiviral activity of GS-6207 and provide a means for rationally developing second-generation therapies.
History
DepositionJan 22, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 21, 2020Provider: repository / Type: Initial release
Revision 1.1Nov 4, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID
Revision 1.2Oct 11, 2023Group: Data collection / Database references ...Data collection / Database references / Refinement description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_ncs_dom_lim
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI ..._chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Capsid protein p24
B: Capsid protein p24
C: Capsid protein p24
hetero molecules


Theoretical massNumber of molelcules
Total (without water)80,42025
Polymers76,3843
Non-polymers4,03622
Water4,270237
1
A: Capsid protein p24
B: Capsid protein p24
hetero molecules

A: Capsid protein p24
B: Capsid protein p24
hetero molecules

A: Capsid protein p24
B: Capsid protein p24
hetero molecules


Theoretical massNumber of molelcules
Total (without water)160,95148
Polymers152,7686
Non-polymers8,18342
Water1086
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_445-y-1,x-y-1,z1
crystal symmetry operation3_545-x+y,-x-1,z1
Buried area23800 Å2
ΔGint-412 kcal/mol
Surface area59010 Å2
MethodPISA
2
C: Capsid protein p24
hetero molecules
x 6


Theoretical massNumber of molelcules
Total (without water)160,61554
Polymers152,7686
Non-polymers7,84748
Water1086
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_345-y-2,x-y-1,z1
crystal symmetry operation3_435-x+y-1,-x-2,z1
crystal symmetry operation4_335-x-2,-y-2,z1
crystal symmetry operation5_545y,-x+y-1,z1
crystal symmetry operation6_455x-y-1,x,z1
Buried area24420 Å2
ΔGint-507 kcal/mol
Surface area58540 Å2
MethodPISA
Unit cell
Length a, b, c (Å)160.050, 160.050, 57.526
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number168
Space group name H-MP6
Space group name HallP6
Symmetry operation#1: x,y,z
#2: x-y,x,z
#3: y,-x+y,z
#4: -y,x-y,z
#5: -x+y,-x,z
#6: -x,-y,z
Components on special symmetry positions
IDModelComponents
11A-457-

HOH

Noncrystallographic symmetry (NCS)NCS domain:
IDEns-ID
11
21
31

NCS domain segments:

Ens-ID: 1

Dom-IDComponent-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11PROPROLEULEU(chain A and (resseq 1:6 or resseq 8:17 or resseq...AA1 - 61 - 6
12GLYGLYPROPRO(chain A and (resseq 1:6 or resseq 8:17 or resseq...AA8 - 178 - 17
13THRTHRPROPRO(chain A and (resseq 1:6 or resseq 8:17 or resseq...AA19 - 8519 - 85
14HISHISPROPRO(chain A and (resseq 1:6 or resseq 8:17 or resseq...AA87 - 9987 - 99
15GLYGLYLEULEU(chain A and (resseq 1:6 or resseq 8:17 or resseq...AA101 - 111101 - 111
16GLUGLULYSLYS(chain A and (resseq 1:6 or resseq 8:17 or resseq...AA113 - 131113 - 131
17TRPTRPILEILE(chain A and (resseq 1:6 or resseq 8:17 or resseq...AA133 - 153133 - 153
18GLNGLNARGARG(chain A and (resseq 1:6 or resseq 8:17 or resseq...AA155 - 173155 - 173
19GLNGLNGLNGLN(chain A and (resseq 1:6 or resseq 8:17 or resseq...AA176 - 179176 - 179
110LYSLYSGLUGLU(chain A and (resseq 1:6 or resseq 8:17 or resseq...AA182 - 187182 - 187
111LEULEUVALVAL(chain A and (resseq 1:6 or resseq 8:17 or resseq...AA189 - 191189 - 191
112ASNASNLEULEU(chain A and (resseq 1:6 or resseq 8:17 or resseq...AA193 - 211193 - 211
113GLUGLUGLNGLN(chain A and (resseq 1:6 or resseq 8:17 or resseq...AA213 - 219213 - 219
21PROPROLEULEU(chain B and (resseq 1:6 or resseq 8:17 or resseq...BB1 - 61 - 6
22GLYGLYPROPRO(chain B and (resseq 1:6 or resseq 8:17 or resseq...BB8 - 178 - 17
23THRTHRPROPRO(chain B and (resseq 1:6 or resseq 8:17 or resseq...BB19 - 8519 - 85
24HISHISPROPRO(chain B and (resseq 1:6 or resseq 8:17 or resseq...BB87 - 9987 - 99
25GLYGLYLEULEU(chain B and (resseq 1:6 or resseq 8:17 or resseq...BB101 - 111101 - 111
26GLUGLULYSLYS(chain B and (resseq 1:6 or resseq 8:17 or resseq...BB113 - 131113 - 131
27TRPTRPILEILE(chain B and (resseq 1:6 or resseq 8:17 or resseq...BB133 - 153133 - 153
28GLNGLNARGARG(chain B and (resseq 1:6 or resseq 8:17 or resseq...BB155 - 173155 - 173
29GLNGLNGLNGLN(chain B and (resseq 1:6 or resseq 8:17 or resseq...BB176 - 179176 - 179
210LYSLYSGLUGLU(chain B and (resseq 1:6 or resseq 8:17 or resseq...BB182 - 187182 - 187
211LEULEUVALVAL(chain B and (resseq 1:6 or resseq 8:17 or resseq...BB189 - 191189 - 191
212ASNASNLEULEU(chain B and (resseq 1:6 or resseq 8:17 or resseq...BB193 - 211193 - 211
213GLUGLUGLNGLN(chain B and (resseq 1:6 or resseq 8:17 or resseq...BB213 - 219213 - 219
31PROPROLEULEU(chain C and (resseq 1:6 or resseq 8:17 or resseq...CC1 - 61 - 6
32GLYGLYPROPRO(chain C and (resseq 1:6 or resseq 8:17 or resseq...CC8 - 178 - 17
33THRTHRPROPRO(chain C and (resseq 1:6 or resseq 8:17 or resseq...CC19 - 8519 - 85
34HISHISPROPRO(chain C and (resseq 1:6 or resseq 8:17 or resseq...CC87 - 9987 - 99
35GLYGLYLEULEU(chain C and (resseq 1:6 or resseq 8:17 or resseq...CC101 - 111101 - 111
36GLUGLULYSLYS(chain C and (resseq 1:6 or resseq 8:17 or resseq...CC113 - 131113 - 131
37TRPTRPILEILE(chain C and (resseq 1:6 or resseq 8:17 or resseq...CC133 - 153133 - 153
38GLNGLNARGARG(chain C and (resseq 1:6 or resseq 8:17 or resseq...CC155 - 173155 - 173
39GLNGLNGLNGLN(chain C and (resseq 1:6 or resseq 8:17 or resseq...CC176 - 179176 - 179
310LYSLYSGLUGLU(chain C and (resseq 1:6 or resseq 8:17 or resseq...CC182 - 187182 - 187
311LEULEUVALVAL(chain C and (resseq 1:6 or resseq 8:17 or resseq...CC189 - 191189 - 191
312ASNASNLEULEU(chain C and (resseq 1:6 or resseq 8:17 or resseq...CC193 - 211193 - 211
313GLUGLUGLNGLN(chain C and (resseq 1:6 or resseq 8:17 or resseq...CC213 - 219213 - 219

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Components

#1: Protein Capsid protein p24 /


Mass: 25461.271 Da / Num. of mol.: 3 / Mutation: A14C, E45C, W184A, M185A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human immunodeficiency virus 1 / Gene: gag / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: B6DRA0, UniProt: P12493*PLUS
#2: Chemical ChemComp-QNG / N-[(1S)-1-(3-{4-chloro-3-[(methylsulfonyl)amino]-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl}-6-[3-methyl-3-(methylsulfonyl)but-1-yn-1-yl]pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl]-2-[(3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl]acetamide / Lenacapavir / Lenacapavir


Mass: 968.282 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C39H32ClF10N7O5S2 / Feature type: SUBJECT OF INVESTIGATION / Comment: medication, antiretroviral*YM
#3: Chemical
ChemComp-IOD / IODIDE ION / Iodide


Mass: 126.904 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: I
#4: Chemical
ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 14 / Source method: obtained synthetically / Formula: Cl
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 237 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.78 Å3/Da / Density % sol: 55.83 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 0.125-0.35M Sodium Iodide, 3-12% Peg 3350, 6% glycerol, 0.1M sodium cacodylate pH 6.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 4.2.2 / Wavelength: 1.00003 Å
DetectorType: RDI CMOS_8M / Detector: CMOS / Date: Nov 9, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.00003 Å / Relative weight: 1
ReflectionResolution: 2.22→46.71 Å / Num. obs: 41892 / % possible obs: 100 % / Redundancy: 10.7 % / Biso Wilson estimate: 29.5368220526 Å2 / CC1/2: 0.994 / Rpim(I) all: 0.101 / Χ2: 1.02 / Net I/σ(I): 8
Reflection shellResolution: 2.22→2.29 Å / Redundancy: 8.6 % / Mean I/σ(I) obs: 1 / Num. unique obs: 3828 / CC1/2: 0.47 / Rpim(I) all: 0.97 / Χ2: 1.03 / % possible all: 99.9

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Processing

Software
NameVersionClassification
PHENIX1.10.1_2155refinement
XDSdata collection
XDSdata reduction
XDSdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6PU1

6pu1


Resolution: 2.22→44.26 Å / SU ML: 0.37 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 30.3
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2685 2051 4.91 %
Rwork0.2314 39694 -
obs0.2332 41745 99.65 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 40.9 Å2
Refinement stepCycle: LAST / Resolution: 2.22→44.26 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5112 0 211 237 5560
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.006677969769195680
X-RAY DIFFRACTIONf_angle_d0.9715361397717837
X-RAY DIFFRACTIONf_chiral_restr0.0534450502844819
X-RAY DIFFRACTIONf_plane_restr0.007036276741969
X-RAY DIFFRACTIONf_dihedral_angle_d24.47125718982101
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.22-2.27170.44161160.42362558X-RAY DIFFRACTION97.4845060153
2.2717-2.32850.360261330.344612602X-RAY DIFFRACTION98.4875765214
2.3285-2.39140.34531600.2992623X-RAY DIFFRACTION99.856476498
2.3914-2.46180.31521000.29092674X-RAY DIFFRACTION100
2.4618-2.54120.3441912969021490.28152610X-RAY DIFFRACTION99.8913830558
2.5412-2.63210.3224737325871290.27092637X-RAY DIFFRACTION99.8555956679
2.6321-2.73740.2989674205971520.26132646X-RAY DIFFRACTION99.9285714286
2.7374-2.8620.2650692650251420.25782630X-RAY DIFFRACTION99.9279019466
2.862-3.01280.3161534894331420.24142635X-RAY DIFFRACTION99.9640028798
3.0128-3.20160.3076457777291550.23442626X-RAY DIFFRACTION100
3.2016-3.44870.2406614007991350.21672646X-RAY DIFFRACTION99.964054637
3.4487-3.79550.2184475131941440.1907666601982667X-RAY DIFFRACTION99.9289015286
3.7955-4.34440.2121417672651220.1748934179262686X-RAY DIFFRACTION99.9644001424
4.3444-5.47180.2172339238241460.1782754706182682X-RAY DIFFRACTION99.8587570621
5.4718-44.260.2402549723791260.217559454262772X-RAY DIFFRACTION99.6218631832

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