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- PDB-8f0f: HIV-1 wild type protease with GRL-110-19A, a chloroacetamide deri... -

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Basic information

Entry
Database: PDB / ID: 8f0f
TitleHIV-1 wild type protease with GRL-110-19A, a chloroacetamide derivative based on Darunavir as P2' group
ComponentsProtease
KeywordsHYDROLASE/INHIBITOR / ASPARTIC ACID PROTEASE / HIV-1 protease / Darunavir / a chloroacetamide derivative inhibitor / ANTIVIRAL PROTEIN / HYDROLASE-INHIBITOR complex
Function / homology
Function and homology information


aspartic-type endopeptidase activity / proteolysis
Similarity search - Function
Retropepsin-like catalytic domain / Retropepsins / Retroviral aspartyl protease / Aspartyl protease, retroviral-type family profile. / Peptidase A2A, retrovirus, catalytic / Aspartic peptidase, active site / Eukaryotic and viral aspartyl proteases active site. / Aspartic peptidase domain superfamily
Similarity search - Domain/homology
Biological speciesHuman immunodeficiency virus 1
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.29 Å
AuthorsWang, Y.-F. / Agniswamy, J. / Ghosh, A.K. / Weber, I.T.
Funding support United States, Japan, 7items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)AI150466 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)AI150461 United States
Department of Energy (DOE, United States)W-31-109-Eng-38 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)Intramural Research Program of the Center for Cancer Research United States
Japan Agency for Medical Research and Development (AMED)JP15fk0410001 Japan
Japan Agency for Medical Research and Development (AMED)JP16fk0410101 Japan
Ministry of Education, Culture, Sports, Science and Technology (Japan)a Grant-in-Aid for Scientific Research (Priority Areas) Japan
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2023
Title: Evaluation of darunavir-derived HIV-1 protease inhibitors incorporating P2' amide-derivatives: Synthesis, biological evaluation and structural studies.
Authors: Ghosh, A.K. / Shahabi, D. / Kipfmiller, M. / Ghosh, A.K. / Johnson, M. / Wang, Y.F. / Agniswamy, J. / Amano, M. / Weber, I.T. / Mitsuya, H.
History
DepositionNov 2, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 15, 2023Provider: repository / Type: Initial release
Revision 1.1Mar 8, 2023Group: Database references / Category: citation / Item: _citation.journal_volume / _citation.title
Revision 1.2Oct 25, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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)22,3278
Polymers21,4812
Non-polymers8466
Water4,089227
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4820 Å2
ΔGint-59 kcal/mol
Surface area9580 Å2
MethodPISA
Unit cell
Length a, b, c (Å)58.419, 86.235, 46.075
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 / Plasmid: pJ414 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: Q5RZ08, HIV-1 retropepsin

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Non-polymers , 5 types, 233 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.: 3 / 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-X7H / (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl [(2S,3R)-4-{[4-(2-chloroacetamido)benzene-1-sulfonyl](2-methylpropyl)amino}-3-hydroxy-1-phenylbutan-2-yl]carbamate


Mass: 624.145 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H38ClN3O8S / Feature type: SUBJECT OF INVESTIGATION
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 227 / 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: 2.7 Å3/Da / Density % sol: 54.47 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 6 / Details: 0.65 M NaCl, 0.1 M Sodium Acetate, pH 6.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-BM / Wavelength: 1 Å
DetectorType: RAYONIX MX300-HS / 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: 1.29→50 Å / Num. obs: 56469 / % possible obs: 95.4 % / Redundancy: 6.8 % / Rmerge(I) obs: 0.052 / Rpim(I) all: 0.021 / Rrim(I) all: 0.057 / Χ2: 1.004 / Net I/σ(I): 14.5 / Num. measured all: 382089
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2CC starRpim(I) allRrim(I) allΧ2% possible all
1.29-1.343.60.63940770.7040.9090.3580.7391.00369.8
1.34-1.395.50.48853370.8660.220.5381.00391.4
1.39-1.457.10.3557260.9530.1390.3771.00898.1
1.45-1.537.10.24657620.9770.0970.2651.00698.4
1.53-1.637.20.16357820.9890.0640.1750.99898.6
1.63-1.757.20.11258160.9940.0440.121.00199.2
1.75-1.937.30.07558760.9970.030.0811.00999.3
1.93-2.217.40.04959090.9990.0190.0520.99799.6
2.21-2.787.40.04359850.9990.0170.0461.00499.8
2.78-5070.03261990.9970.0130.0351.00799.4

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation5.3 Å34.69 Å
Translation5.3 Å34.69 Å

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Processing

Software
NameVersionClassificationNB
HKL-2000data reduction
HKL-2000data scaling
PHASER4.064 Datablock id: mmcif_pdbx.dicphasing
REFMAC5.8.0352refinement
PDB_EXTRACT3.27data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6VOD

6vod


Resolution: 1.29→34.72 Å / Cor.coef. Fo:Fc: 0.973 / Cor.coef. Fo:Fc free: 0.965 / SU B: 1.289 / SU ML: 0.024 / SU R Cruickshank DPI: 0.0415 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.041 / ESU R Free: 0.042 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.1626 2771 4.9 %RANDOM
Rwork0.1316 ---
obs0.1331 53658 95.28 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 82.92 Å2 / Biso mean: 14.078 Å2 / Biso min: 4.01 Å2
Baniso -1Baniso -2Baniso -3
1--0.15 Å20 Å20 Å2
2---0.46 Å20 Å2
3---0.6 Å2
Refinement stepCycle: final / Resolution: 1.29→34.72 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1512 0 92 227 1831
Biso mean--12.29 24.84 -
Num. residues----198
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0130.0121827
X-RAY DIFFRACTIONr_bond_other_d0.0080.0161846
X-RAY DIFFRACTIONr_angle_refined_deg1.9261.7072526
X-RAY DIFFRACTIONr_angle_other_deg0.6771.6144346
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.9415251
X-RAY DIFFRACTIONr_dihedral_angle_2_deg5.041510
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.89310345
X-RAY DIFFRACTIONr_chiral_restr0.1330.2306
X-RAY DIFFRACTIONr_gen_planes_refined0.010.022042
X-RAY DIFFRACTIONr_gen_planes_other0.0030.02336
X-RAY DIFFRACTIONr_rigid_bond_restr4.80233671
LS refinement shellResolution: 1.291→1.325 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.342 153 -
Rwork0.307 2703 -
all-2856 -
obs--65.72 %

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