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- PDB-5upz: HIV-1 wild Type protease with GRL-0518A , an isophthalamide-deriv... -

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Basic information

Entry
Database: PDB / ID: 5upz
TitleHIV-1 wild Type protease with GRL-0518A , an isophthalamide-derived P2-P3 ligand with the para-hydoxymethyl sulfonamide isostere as the P2' group
ComponentsProtease
Keywordshydrolase/hydrolase inhibitor / an isophthalamide-derived P2-P3 ligand / HIV-1 protease inhibitor GRL-0518A / darunavir / multidrug-resistant / hydrolase inhibitor complex / hydrolase-hydrolase inhibitor complex
Function / homology
Function and homology information


HIV-1 retropepsin / symbiont-mediated activation of host apoptosis / retroviral ribonuclease H / exoribonuclease H / exoribonuclease H activity / host multivesicular body / DNA integration / viral genome integration into host DNA / RNA-directed DNA polymerase / establishment of integrated proviral latency ...HIV-1 retropepsin / symbiont-mediated activation of host apoptosis / retroviral ribonuclease H / exoribonuclease H / exoribonuclease H activity / host multivesicular body / DNA integration / viral genome integration into host DNA / RNA-directed DNA polymerase / establishment of integrated proviral latency / symbiont-mediated suppression of host gene expression / viral penetration into host nucleus / RNA stem-loop binding / RNA-directed DNA polymerase activity / RNA-DNA hybrid ribonuclease activity / Transferases; Transferring phosphorus-containing groups; Nucleotidyltransferases / host cell / 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 / viral translational frameshifting / lipid binding / host cell nucleus / host cell plasma membrane / structural molecule activity / virion membrane / 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. / Retropepsin-like catalytic domain / RNase H type-1 domain profile. / Ribonuclease H domain / Matrix protein, lentiviral and alpha-retroviral, N-terminal / Retroviral nucleocapsid Gag protein p24, C-terminal domain / Gag protein p24 C-terminal domain / Reverse transcriptase domain / Reverse transcriptase (RT) catalytic domain profile. / Retropepsins / Retroviral aspartyl protease / Aspartyl protease, retroviral-type family profile. / Peptidase A2A, retrovirus, catalytic / Reverse transcriptase (RNA-dependent DNA polymerase) / Retroviral matrix protein / Retrovirus capsid, C-terminal / 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-8HD / Protease / Gag-Pol polyprotein
Similarity search - Component
Biological speciesHuman immunodeficiency virus 1
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.27 Å
AuthorsWang, Y.-F. / Agniswamy, J. / Weber, I.T.
Funding support United States, Japan, 8items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM53386 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM62920 United States
Department of Energy (DOE, United States)No. W-31-109-Eng-38 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)the Intramural Research Program of the Center for Cancer Research United States
Ministry of Education, Culture, Sports, Science and Technology (Japan)a Grant-in-Aid for Scientific Research (Priority Areas) Japan
he Ministry of Health, Welfare, and Labora Grant for Promotion of AIDS Research Japan
Ministry of Education, Culture, Sports, Science and Technology (Japan)the Grant to the Cooperative Research Project on Clinical and Epidemiological Studies of Emerging and Reemerging Infectious Diseases (Renkei Jigyo) Japan
Purdue Universitythe Purdue University Center for Cancer Research United States
CitationJournal: Bioorg. Med. Chem. / Year: 2017
Title: Design of novel HIV-1 protease inhibitors incorporating isophthalamide-derived P2-P3 ligands: Synthesis, biological evaluation and X-ray structural studies of inhibitor-HIV-1 protease complex.
Authors: Ghosh, A.K. / Brindisi, M. / Nyalapatla, P.R. / Takayama, J. / Ella-Menye, J.R. / Yashchuk, S. / Agniswamy, J. / Wang, Y.F. / Aoki, M. / Amano, M. / Weber, I.T. / Mitsuya, H.
History
DepositionFeb 5, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 10, 2017Provider: repository / Type: Initial release
Revision 1.1Sep 27, 2017Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.2Oct 4, 2017Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Dec 4, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.4Oct 4, 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 / diffrn_radiation_wavelength / 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.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_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)22,48110
Polymers21,4812
Non-polymers9998
Water4,756264
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5090 Å2
ΔGint-68 kcal/mol
Surface area9480 Å2
MethodPISA
Unit cell
Length a, b, c (Å)58.175, 86.418, 45.828
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP21212
Components on special symmetry positions
IDModelComponents
11B-260-

HOH

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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: pET11a / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: C8B467, UniProt: P03366*PLUS

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Non-polymers , 5 types, 272 molecules

#2: Chemical ChemComp-8HD / N~3~-{(2S,3R)-3-hydroxy-4-[{[4-(hydroxymethyl)phenyl]sulfonyl}(2-methylpropyl)amino]-1-phenylbutan-2-yl}-N~1~-methyl-N~1~-[(4-methyl-1,3-oxazol-2-yl)methyl]benzene-1,3-dicarboxamide


Mass: 662.796 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C35H42N4O7S
#3: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Na
#4: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Cl
#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.: 264 / Source method: isolated from a natural source / Formula: H2O

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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: 2.68 Å3/Da / Density % sol: 54.1 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 5 / Details: 1.24 M NaCl, 0.1 M Sodium Acetate, pH 5.0 / PH range: 5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-BM / Wavelength: 1 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Nov 20, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.27→50 Å / Num. obs: 57235 / % possible obs: 91.8 % / Redundancy: 6.2 % / Rmerge(I) obs: 0.054 / Net I/σ(I): 26.5
Reflection shellResolution: 1.27→1.32 Å / Redundancy: 2 % / Rmerge(I) obs: 0.351 / Mean I/σ(I) obs: 2.2 / Num. unique obs: 3123 / % possible all: 51

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Processing

Software
NameClassification
HKL-2000data reduction
HKL-2000data scaling
AMoREphasing
SHELXL-97refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3DJK

3djk


Resolution: 1.27→50 Å / Cross valid method: FREE R-VALUE / σ(F): 0
Details: ANISOTROPIC REFINEMENT REDUCED FREE R (NO CUTOFF) BY ?
RfactorNum. reflection% reflectionSelection details
Rfree0.198 2845 5 %RANDOM
Rwork0.1445 ---
all0.1471 ---
obs-56943 92.3 %-
Refine analyzeNum. disordered residues: 60 / Occupancy sum hydrogen: 0 / Occupancy sum non hydrogen: 1761.95
Refinement stepCycle: LAST / Resolution: 1.27→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1512 0 47 281 1840
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONs_bond_d0.012
X-RAY DIFFRACTIONs_angle_d0.03
X-RAY DIFFRACTIONs_similar_dist0
X-RAY DIFFRACTIONs_from_restr_planes0.0308
X-RAY DIFFRACTIONs_zero_chiral_vol0.068
X-RAY DIFFRACTIONs_non_zero_chiral_vol0.085
X-RAY DIFFRACTIONs_anti_bump_dis_restr0.014
X-RAY DIFFRACTIONs_rigid_bond_adp_cmpnt0.004
X-RAY DIFFRACTIONs_similar_adp_cmpnt0.051
X-RAY DIFFRACTIONs_approx_iso_adps0.084

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