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- PDB-8fuj: HIV-1 wild type protease with GRL-03419A, with N-(2,5-dimethylphe... -

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Basic information

Entry
Database: PDB / ID: 8fuj
TitleHIV-1 wild type protease with GRL-03419A, with N-(2,5-dimethylphenyl)-4-(pyridin-3-yl)pyrimidin-2-amine as P2-P3 group and 3,5-difluorophenylmethyl as the P1 group
ComponentsProtease
KeywordsHYDROLASE/INHIBITOR / ASPARTIC ACID PROTEASE / HIV-1 PROTEASE / INHIBITORS / pyridylpyrimidine / HYDROLASE-INHIBITOR complex
Function / homology
Function and homology information


host multivesicular body / aspartic-type endopeptidase activity / virion membrane / 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
FORMIC ACID / Chem-Y9N / Protease
Similarity search - Component
Biological speciesHuman immunodeficiency virus 1
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.12 Å
AuthorsWang, Y.-F. / Agniswamy, J. / Ghosh, A.K. / Weber, I.T.
Funding support United States, 2items
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
CitationJournal: Eur.J.Med.Chem. / Year: 2023
Title: Exploration of imatinib and nilotinib-derived templates as the P2-Ligand for HIV-1 protease inhibitors: Design, synthesis, protein X-ray structural studies, and biological evaluation.
Authors: Ghosh, A.K. / Mishevich, J.L. / Kovela, S. / Shaktah, R. / Ghosh, A.K. / Johnson, M. / Wang, Y.F. / Wong-Sam, A. / Agniswamy, J. / Amano, M. / Takamatsu, Y. / Hattori, S.I. / Weber, I.T. / Mitsuya, H.
History
DepositionJan 17, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 24, 2023Provider: repository / Type: Initial release
Revision 1.1May 22, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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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)22,56111
Polymers21,4812
Non-polymers1,0809
Water5,621312
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5180 Å2
ΔGint-71 kcal/mol
Surface area9760 Å2
MethodPISA
Unit cell
Length a, b, c (Å)58.609, 86.214, 46.189
Angle α, β, γ (deg.)90.00, 90.00, 90.00
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 / Strain: isolate BRU/LAI / Gene: pol / Plasmid: pJ414 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: Q5RZ08, HIV-1 retropepsin

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Non-polymers , 6 types, 321 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.: 4 / Source method: obtained synthetically / Formula: Cl
#4: Chemical ChemComp-FMT / FORMIC ACID


Mass: 46.025 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: CH2O2
#5: Chemical ChemComp-Y9N / N-{(2S,3R)-1-(3,5-difluorophenyl)-3-hydroxy-4-[(4-methoxybenzene-1-sulfonyl)(2-methylpropyl)amino]butan-2-yl}-4-methyl-3-{[(4M)-4-(pyridin-3-yl)pyrimidin-2-yl]amino}benzamide


Mass: 730.823 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C38H40F2N6O5S
#6: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 312 / 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: 54.48 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 6
Details: 0.57M sodium chloride and 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-ID / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Jun 5, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.12→50 Å / Num. obs: 84494 / % possible obs: 93.4 % / Redundancy: 5.5 % / Biso Wilson estimate: 6.894 Å2 / Rmerge(I) obs: 0.068 / Χ2: 0.037 / Net I/σ(I): 16.9
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsΧ2Diffraction-ID% possible all
1.12-1.161.70.33750021156.1
1.16-1.212.30.30972800.995181.7
1.21-1.264.10.29286690.998196.7
1.26-1.336.10.2689511.0051100
1.33-1.416.30.19489790.998199.9
1.41-1.525.90.12689621.001199.8
1.52-1.676.70.08590210.9971100
1.67-1.926.40.0690790.997199.9
1.92-2.416.30.04890931.001199.8
2.41-506.30.04694580.995199.7

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Processing

Software
NameVersionClassification
REFMAC5.8.0352refinement
HKL-2000data scaling
HKL-2000data reduction
PHASER4.064phasing
PDB_EXTRACT4data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.12→36.3 Å / Cor.coef. Fo:Fc: 0.979 / Cor.coef. Fo:Fc free: 0.975 / SU B: 0.723 / SU ML: 0.015 / Cross valid method: THROUGHOUT / ESU R: 0.027 / ESU R Free: 0.027 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.13584 4124 4.9 %RANDOM
Rwork0.1206 ---
obs0.12135 80315 93.35 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 10.509 Å2
Baniso -1Baniso -2Baniso -3
1-0.33 Å20 Å2-0 Å2
2---0.21 Å20 Å2
3----0.12 Å2
Refinement stepCycle: 1 / Resolution: 1.12→36.3 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1512 0 69 312 1893
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.0122023
X-RAY DIFFRACTIONr_bond_other_d0.0040.0162051
X-RAY DIFFRACTIONr_angle_refined_deg1.9431.7172812
X-RAY DIFFRACTIONr_angle_other_deg0.7821.6074824
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.9145281
X-RAY DIFFRACTIONr_dihedral_angle_2_deg4.265511
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.34610386
X-RAY DIFFRACTIONr_dihedral_angle_4_deg
X-RAY DIFFRACTIONr_chiral_restr0.1280.2327
X-RAY DIFFRACTIONr_gen_planes_refined0.0140.022297
X-RAY DIFFRACTIONr_gen_planes_other0.0160.02383
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.3070.861929
X-RAY DIFFRACTIONr_mcbond_other1.3070.862930
X-RAY DIFFRACTIONr_mcangle_it1.721.3061188
X-RAY DIFFRACTIONr_mcangle_other1.721.3071189
X-RAY DIFFRACTIONr_scbond_it2.9051.2221094
X-RAY DIFFRACTIONr_scbond_other2.9011.2211091
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other3.2761.6851585
X-RAY DIFFRACTIONr_long_range_B_refined3.14918.8662171
X-RAY DIFFRACTIONr_long_range_B_other3.00414.2952081
X-RAY DIFFRACTIONr_rigid_bond_restr5.64334074
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.121→1.15 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.357 169 -
Rwork0.303 3278 -
obs--52.04 %

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