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- PDB-6vce: HIV-1 wild type protease with GRL-026-18A, a crown-like tetrahydr... -

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Basic information

Entry
Database: PDB / ID: 6vce
TitleHIV-1 wild type protease with GRL-026-18A, a crown-like tetrahydropyranotetrahydrofuran with a bridged methylene group as a P2 ligand
ComponentsProtease
KeywordsHYDROLASE/HYDROLASE INHIBITOR / ASPARTIC ACID PROTEASE / HIV-1 PROTEASE / cyclic ethers / urethane / carboxamide / inhibitors / multidrug-resistant / synthesis / X-ray crystal structure / backbone binding / VIRAL PROTEIN / HYDROLASE-HYDROLASE INHIBITOR complex
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
Chem-G6R / Gag-Pol polyprotein / Protease
Similarity search - Component
Biological speciesHuman immunodeficiency virus 1
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.18 Å
AuthorsWang, Y.-F. / Kneller, D.W. / Weber, I.T.
Funding support United States, Japan, 8items
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
Other government United States
Other government Japan
Other government Japan
Other government Japan
CitationJournal: Acs Med.Chem.Lett. / Year: 2020
Title: Design, Synthesis, and X-ray Studies of Potent HIV-1 Protease Inhibitors with P2-Carboxamide Functionalities.
Authors: Ghosh, A.K. / Grillo, A. / Raghavaiah, J. / Kovela, S. / Johnson, M.E. / Kneller, D.W. / Wang, Y.F. / Hattori, S.I. / Higashi-Kuwata, N. / Weber, I.T. / Mitsuya, H.
History
DepositionDec 20, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 1, 2020Provider: repository / Type: Initial release
Revision 1.1Nov 4, 2020Group: Database references / Derived calculations
Category: citation / citation_author ...citation / citation_author / pdbx_struct_conn_angle / struct_conn
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 / _citation_author.name / _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
Revision 1.2Oct 11, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Protease
B: Protease
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,60612
Polymers21,4812
Non-polymers1,12510
Water4,053225
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5380 Å2
ΔGint-86 kcal/mol
Surface area9570 Å2
MethodPISA
Unit cell
Length a, b, c (Å)58.904, 86.207, 46.090
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
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human immunodeficiency virus 1 / Gene: pol / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: Q5RZ08, UniProt: P03367*PLUS

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Non-polymers , 5 types, 235 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.: 6 / Source method: obtained synthetically / Formula: Cl
#4: Chemical ChemComp-G6R / N-[(2S,3R)-4-[{[2-(cyclopropylamino)-1,3-benzothiazol-6-yl]sulfonyl}(2-methylpropyl)amino]-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl]-2-[(3S,3aR,5S,7aS,8S)-hexahydro-4H-3,5-methanofuro[2,3-b]pyran-8-yl]acetamide


Mass: 704.847 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C34H42F2N4O6S2 / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 225 / 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: 2.72 Å3/Da / Density % sol: 54.84 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 6.2
Details: 1.8 M sodium chloride, 0.1 M sodium acetate pH 6.2; Starting protein concentration was 4.2 mg/mL and inhibitors were complexed at 5:1 molar ratio

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Data collection

DiffractionMean temperature: 90 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-ID / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Aug 10, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.18→50 Å / Num. obs: 72509 / % possible obs: 93.6 % / Redundancy: 5.6 % / Rmerge(I) obs: 0.082 / Rpim(I) all: 0.035 / Rrim(I) all: 0.09 / Χ2: 1.002 / Net I/σ(I): 12.2 / Num. measured all: 403399
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
1.18-1.222.10.35842380.80.2510.4411.00355.5
1.22-1.272.80.35664390.8460.2190.4221.00484.2
1.27-1.334.90.35975440.9210.1750.4010.98998.6
1.33-1.46.10.31176600.9620.1360.341.00799.6
1.4-1.496.20.23976540.9760.1040.2611.0199.7
1.49-1.65.90.15876560.9850.070.1731.0199.4
1.6-1.766.60.11976980.9910.050.1291.00499.6
1.76-2.026.30.08977550.9930.0380.0971.00299.7
2.02-2.546.30.07777890.9940.0330.0841.00199.3
2.54-506.30.06980760.9950.030.0750.99199.3

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation5.32 Å33.45 Å
Translation5.32 Å33.45 Å

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Processing

Software
NameVersionClassification
REFMAC5.8.0253refinement
HKL-20000.716.1data reduction
HKL-20000.716.1data scaling
PHASER4.064 Datablock id: mmcif_pdbx.dicphasing
PDB_EXTRACT3.25data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3NU3

3nu3


Resolution: 1.18→33.48 Å / Cor.coef. Fo:Fc: 0.977 / Cor.coef. Fo:Fc free: 0.974 / SU B: 1.196 / SU ML: 0.023 / SU R Cruickshank DPI: 0.0336 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.034 / ESU R Free: 0.033
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.1553 3516 4.9 %RANDOM
Rwork0.1356 ---
obs0.1365 68939 93.36 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 80.88 Å2 / Biso mean: 15.273 Å2 / Biso min: 7.57 Å2
Baniso -1Baniso -2Baniso -3
1--1.47 Å2-0 Å2-0 Å2
2---0.42 Å20 Å2
3---1.89 Å2
Refinement stepCycle: final / Resolution: 1.18→33.48 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1512 0 115 225 1852
Biso mean--12.23 24.69 -
Num. residues----198
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0210.0131883
X-RAY DIFFRACTIONr_bond_other_d0.0020.0171933
X-RAY DIFFRACTIONr_angle_refined_deg2.5591.7272600
X-RAY DIFFRACTIONr_angle_other_deg1.7151.6434527
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.8035252
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.98422.31969
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.25615346
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.5071510
X-RAY DIFFRACTIONr_chiral_restr0.2560.2280
X-RAY DIFFRACTIONr_gen_planes_refined0.0130.022036
X-RAY DIFFRACTIONr_gen_planes_other0.0030.02354
X-RAY DIFFRACTIONr_rigid_bond_restr7.63333816
LS refinement shellResolution: 1.181→1.212 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.318 137 -
Rwork0.309 2729 -
all-2866 -
obs--50.67 %

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