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- PDB-6vod: HIV-1 wild type protease with GRL-052-16A, a tricyclic cyclohexan... -

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Basic information

Entry
Database: PDB / ID: 6vod
TitleHIV-1 wild type protease with GRL-052-16A, a tricyclic cyclohexane fused tetrahydrofuranofuran (CHf-THF) derivative as the P2 ligand
ComponentsProtease
KeywordsANTIVIRAL PROTEIN / inhibitors / antiviral / multidrug-resistant / Chf-THF / backbone binding
Function / homology
Function and homology information


HIV-1 retropepsin / retroviral ribonuclease H / exoribonuclease H / exoribonuclease H activity / host multivesicular body / DNA integration / viral genome integration into host DNA / RNA-directed DNA polymerase / viral penetration into host nucleus / establishment of integrated proviral latency ...HIV-1 retropepsin / retroviral ribonuclease H / exoribonuclease H / exoribonuclease H activity / host multivesicular body / DNA integration / viral genome integration into host DNA / RNA-directed DNA polymerase / viral penetration into host nucleus / establishment of integrated proviral latency / RNA stem-loop binding / RNA-directed DNA polymerase activity / host cell / RNA-DNA hybrid ribonuclease activity / Transferases; Transferring phosphorus-containing groups; Nucleotidyltransferases / symbiont-mediated suppression of host gene expression / viral nucleocapsid / DNA recombination / DNA-directed DNA polymerase / Hydrolases; Acting on ester bonds / aspartic-type endopeptidase activity / DNA-directed DNA polymerase activity / symbiont entry into host cell / lipid binding / host cell nucleus / host cell plasma membrane / virion membrane / structural molecule activity / proteolysis / DNA binding / zinc ion binding / membrane
Similarity search - Function
Reverse transcriptase connection / Reverse transcriptase connection domain / Reverse transcriptase thumb / Reverse transcriptase thumb domain / Integrase Zinc binding domain / Zinc finger integrase-type profile. / Integrase-like, N-terminal / Integrase DNA binding domain / Integrase, C-terminal domain superfamily, retroviral / Integrase, N-terminal zinc-binding domain ...Reverse transcriptase connection / Reverse transcriptase connection domain / Reverse transcriptase thumb / Reverse transcriptase thumb domain / Integrase Zinc binding domain / Zinc finger integrase-type profile. / Integrase-like, N-terminal / Integrase DNA binding domain / Integrase, C-terminal domain superfamily, retroviral / Integrase, N-terminal zinc-binding domain / Integrase, C-terminal, retroviral / Integrase DNA binding domain profile. / Immunodeficiency lentiviral matrix, N-terminal / gag gene protein p17 (matrix protein) / RNase H / Integrase core domain / Integrase, catalytic core / Integrase catalytic domain profile. / Retroviral nucleocapsid Gag protein p24, C-terminal domain / Gag protein p24 C-terminal domain / Retropepsin-like catalytic domain / Matrix protein, lentiviral and alpha-retroviral, N-terminal / Ribonuclease H domain / RNase H type-1 domain profile. / Reverse transcriptase (RNA-dependent DNA polymerase) / Reverse transcriptase domain / Reverse transcriptase (RT) catalytic domain profile. / Retropepsins / Retroviral aspartyl protease / Aspartyl protease, retroviral-type family profile. / Peptidase A2A, retrovirus, catalytic / Retrovirus capsid, C-terminal / Retroviral matrix protein / Retrovirus capsid, N-terminal / zinc finger / Zinc knuckle / Zinc finger, CCHC-type superfamily / Cathepsin D, subunit A; domain 1 / Acid Proteases / Zinc finger, CCHC-type / Zinc finger CCHC-type profile. / Aspartic peptidase, active site / Eukaryotic and viral aspartyl proteases active site. / Ribonuclease H superfamily / Aspartic peptidase domain superfamily / Ribonuclease H-like superfamily / Reverse transcriptase/Diguanylate cyclase domain / DNA/RNA polymerase superfamily / Beta Barrel / Mainly Beta
Similarity search - Domain/homology
FORMIC ACID / Chem-T1R / Gag-Pol polyprotein / Protease
Similarity search - Component
Biological speciesHuman immunodeficiency virus 1
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.25 Å
AuthorsWang, Y.-F. / Agniswamy, J. / Weber, I.T.
Funding support United States, Japan, 5items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)AI150466 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)AI150461 United States
Japan Agency for Medical Research and Development (AMED)JP15fk0410001 Japan
Japan Agency for Medical Research and Development (AMED)JP16fk0410101 Japan
National Institutes of Health/National Cancer Institute (NIH/NCI)The Intramural Research Program of the Center for Cancer Research United States
CitationJournal: J.Med.Chem. / Year: 2020
Title: Structure-Based Design of Highly Potent HIV-1 Protease Inhibitors Containing New Tricyclic Ring P2-Ligands: Design, Synthesis, Biological, and X-ray Structural Studies.
Authors: Ghosh, A.K. / Kovela, S. / Osswald, H.L. / Amano, M. / Aoki, M. / Agniswamy, J. / Wang, Y.F. / Weber, I.T. / Mitsuya, H.
History
DepositionJan 30, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 13, 2020Provider: repository / Type: Initial release
Revision 1.1May 27, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Oct 11, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / pdbx_struct_conn_angle / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr2_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Protease
B: Protease
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,3028
Polymers21,4812
Non-polymers8216
Water3,999222
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4790 Å2
ΔGint-49 kcal/mol
Surface area9630 Å2
MethodPISA
Unit cell
Length a, b, c (Å)58.784, 86.209, 46.015
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP21212

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein Protease


Mass: 10740.677 Da / Num. of mol.: 2 / Mutation: Q7K, L33I, L63I, C67A, C95A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human immunodeficiency virus 1 / Gene: pol / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / References: UniProt: Q5RZ08, UniProt: P03367*PLUS

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Non-polymers , 6 types, 228 molecules

#2: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#3: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#5: Chemical ChemComp-T1R / (1R,3aS,5R,6S,7aR)-octahydro-1,6-epoxy-2-benzofuran-5-yl [(2S,3R)-3-hydroxy-4-{[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino}-1-phenylbutan-2-yl]carbamate


Mass: 588.712 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C30H40N2O8S / Feature type: SUBJECT OF INVESTIGATION
#6: Chemical ChemComp-FMT / FORMIC ACID


Mass: 46.025 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: CH2O2
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 222 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.71 Å3/Da / Density % sol: 54.68 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 6 / Details: 0.65M NaCl, 0.1M Sodeum acetate pH 6.0

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Data collection

DiffractionMean temperature: 90 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-BM / Wavelength: 1 Å
DetectorType: RAYONIX MX300HE / Detector: CCD / Date: Dec 11, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.25→50 Å / Num. obs: 58388 / % possible obs: 89.4 % / Redundancy: 6.4 % / Biso Wilson estimate: 12.511 Å2 / Rmerge(I) obs: 0.079 / Rpim(I) all: 0.034 / Rrim(I) all: 0.086 / Χ2: 1.001 / Net I/σ(I): 15.9
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
1.25-1.293.20.51832020.7290.3120.6111.00749.9
1.29-1.354.20.4541780.8370.2360.5121.00564.7
1.35-1.415.30.33855580.9380.1550.3730.99586.2
1.41-1.486.80.22863490.9750.0920.2460.99698
1.48-1.5770.16363810.9880.0650.176198.5
1.57-1.77.10.12364140.9910.0490.1321.00898.8
1.7-1.877.20.09364660.9940.0370.11.00299.2
1.87-2.147.30.0765240.9960.0280.075199.5
2.14-2.697.40.06365960.9970.0250.0681.00199.8
2.69-506.50.06967200.9690.0330.0770.99797.7

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation5.27 Å33.4 Å
Translation5.27 Å33.4 Å

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Processing

Software
NameVersionClassification
HKL-20000.719.2data reduction
HKL-20000.72data scaling
PHASER4.064 Datablock id: mmcif_pdbx.dicphasing
REFMAC5.8.0258refinement
PDB_EXTRACT3.25data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3NU3

3nu3


Resolution: 1.25→33.43 Å / Cor.coef. Fo:Fc: 0.938 / Cor.coef. Fo:Fc free: 0.933 / SU B: 1.245 / SU ML: 0.024 / SU R Cruickshank DPI: 0.0484 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.048 / ESU R Free: 0.046
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.1847 2991 5.1 %RANDOM
Rwork0.1591 ---
obs0.1604 55357 89.09 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 74.6 Å2 / Biso mean: 14.916 Å2 / Biso min: 5.79 Å2
Baniso -1Baniso -2Baniso -3
1-0.14 Å2-0 Å20 Å2
2---0.11 Å2-0 Å2
3----0.04 Å2
Refinement stepCycle: final / Resolution: 1.25→33.43 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1512 0 94 222 1828
Biso mean--12.15 24.38 -
Num. residues----198
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.020.0131821
X-RAY DIFFRACTIONr_bond_other_d0.0010.0171865
X-RAY DIFFRACTIONr_angle_refined_deg2.3131.7112509
X-RAY DIFFRACTIONr_angle_other_deg1.4731.6384360
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.1835246
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.38922.31969
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.63715339
X-RAY DIFFRACTIONr_dihedral_angle_4_deg12.4441510
X-RAY DIFFRACTIONr_chiral_restr0.1470.2271
X-RAY DIFFRACTIONr_gen_planes_refined0.0120.021983
X-RAY DIFFRACTIONr_gen_planes_other0.0030.02353
X-RAY DIFFRACTIONr_rigid_bond_restr4.36633686
LS refinement shellResolution: 1.25→1.282 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.371 109 -
Rwork0.358 2056 -
all-2165 -
obs--45.28 %

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