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- PDB-5kao: Crystal structure of wild type HIV-1 protease in complex with GRL... -

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Basic information

Entry
Database: PDB / ID: 5kao
TitleCrystal structure of wild type HIV-1 protease in complex with GRL-10413
Componentsprotease
KeywordsHYDROLASE/HYDROLASE INHIBITOR / GRL-10413 / HIV-1 PROTEASE / PROTEASE-INHIBITOR / DARUNAVIR / 2-CHLOROANISOLE / NONPEPTIDIC / HYDROLASE-HYDROLASE INHIBITOR COMPLEX
Function / homology
Function and homology information


integrase activity / Integration of viral DNA into host genomic DNA / Autointegration results in viral DNA circles / Minus-strand DNA synthesis / Plus-strand DNA synthesis / 2-LTR circle formation / Uncoating of the HIV Virion / Early Phase of HIV Life Cycle / Vpr-mediated nuclear import of PICs / Integration of provirus ...integrase activity / Integration of viral DNA into host genomic DNA / Autointegration results in viral DNA circles / Minus-strand DNA synthesis / Plus-strand DNA synthesis / 2-LTR circle formation / Uncoating of the HIV Virion / Early Phase of HIV Life Cycle / Vpr-mediated nuclear import of PICs / Integration of provirus / APOBEC3G mediated resistance to HIV-1 infection / Binding and entry of HIV virion / viral life cycle / HIV-1 retropepsin / symbiont-mediated activation of host apoptosis / Assembly Of The HIV Virion / retroviral ribonuclease H / exoribonuclease H / exoribonuclease H activity / Budding and maturation of HIV virion / host multivesicular body / protein processing / 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 / peptidase activity / 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 / identical protein 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-G43 / Gag-Pol polyprotein / Pol polyprotein
Similarity search - Component
Biological speciesHuman immunodeficiency virus 1
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.8 Å
AuthorsYedidi, R.S. / Delino, N.S. / Das, D. / Kaufman, J.D. / Wingfield, P.T. / Ghosh, A.K. / Mitsuya, H.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI) United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
CitationJournal: Antimicrob.Agents Chemother. / Year: 2016
Title: A Modified P1 Moiety Enhances In Vitro Antiviral Activity against Various Multidrug-Resistant HIV-1 Variants and In Vitro Central Nervous System Penetration Properties of a Novel Nonpeptidic ...Title: A Modified P1 Moiety Enhances In Vitro Antiviral Activity against Various Multidrug-Resistant HIV-1 Variants and In Vitro Central Nervous System Penetration Properties of a Novel Nonpeptidic Protease Inhibitor, GRL-10413.
Authors: Amano, M. / Salcedo-Gomez, P.M. / Zhao, R. / Yedidi, R.S. / Das, D. / Bulut, H. / Delino, N.S. / Sheri, V.R. / Ghosh, A.K. / Mitsuya, H.
History
DepositionJun 1, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 31, 2016Provider: repository / Type: Initial release
Revision 1.1Sep 28, 2016Group: Database references
Revision 1.2Dec 7, 2016Group: Database references
Revision 1.3Sep 27, 2017Group: Author supporting evidence / Database references / Category: citation / pdbx_audit_support
Item: _citation.journal_id_CSD / _pdbx_audit_support.funding_organization
Revision 1.4Dec 4, 2019Group: Author supporting evidence / Database references / Category: pdbx_audit_support / struct_ref_seq_dif / Item: _struct_ref_seq_dif.details
Revision 1.5Sep 27, 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)22,0783
Polymers21,4512
Non-polymers6271
Water2,522140
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4020 Å2
ΔGint-21 kcal/mol
Surface area9460 Å2
MethodPISA
Unit cell
Length a, b, c (Å)50.650, 57.675, 61.558
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein protease


Mass: 10725.599 Da / Num. of mol.: 2 / Mutation: C67A, C95A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human immunodeficiency virus 1 / Gene: pol / Production host: Escherichia coli (E. coli) / References: UniProt: Q72874, UniProt: P04585*PLUS
#2: Chemical ChemComp-G43 / [(3~{a}~{S},4~{R},6~{a}~{R})-2,3,3~{a},4,5,6~{a}-hexahydrofuro[2,3-b]furan-4-yl] ~{N}-[(2~{S},3~{R})-1-(3-chloranyl-4-methoxy-phenyl)-4-[(4-methoxyphenyl)sulfonyl-(2-methylpropyl)amino]-3-oxidanyl-butan-2-yl]carbamate


Mass: 627.146 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H39ClN2O9S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 140 / 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: 2.1 Å3/Da / Density % sol: 41.31 % / Description: Rod shape
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 5
Details: 0.1 M citric acid buffer at pH 5.0 with ammonium sulfate as precipitant

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Data collection

DiffractionMean temperature: 95 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-ID / Wavelength: 1 Å
DetectorType: RAYONIX MX-300 / Detector: CCD / Date: Nov 14, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.68→50 Å / Num. obs: 18748 / % possible obs: 89.4 % / Redundancy: 2.1 % / Rmerge(I) obs: 0.093 / Rsym value: 0.093 / Net I/av σ(I): 16.011 / Net I/σ(I): 8.2
Reflection shellResolution: 1.68→1.71 Å / Redundancy: 1.5 % / Rmerge(I) obs: 0.331 / Mean I/σ(I) obs: 1.795 / % possible all: 75.6

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Phasing

PhasingMethod: molecular replacement
Phasing MR
Highest resolutionLowest resolution
Rotation1.72 Å26.56 Å
Translation1.72 Å26.56 Å

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Processing

Software
NameVersionClassification
HKL-2000data collection
HKL-2000data scaling
MOLREP10.2.35phasing
PHENIXrefinement
PDB_EXTRACT3.2data extraction
HKL-2000data reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4HLA

4hla


Resolution: 1.8→32.371 Å / SU ML: 0.17 / Cross valid method: FREE R-VALUE / σ(F): 1.23 / Phase error: 20.93
RfactorNum. reflection% reflection
Rfree0.2209 789 5.09 %
Rwork0.1838 --
obs0.1856 15506 89.75 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 62.62 Å2 / Biso mean: 19.6055 Å2 / Biso min: 7.08 Å2
Refinement stepCycle: final / Resolution: 1.8→32.371 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1510 0 50 140 1700
Biso mean--15.98 30.29 -
Num. residues----198
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0091594
X-RAY DIFFRACTIONf_angle_d1.2032167
X-RAY DIFFRACTIONf_chiral_restr0.052257
X-RAY DIFFRACTIONf_plane_restr0.006266
X-RAY DIFFRACTIONf_dihedral_angle_d14.433590
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.8-1.91280.25961500.19052476X-RAY DIFFRACTION93
1.9128-2.06040.24631420.17822483X-RAY DIFFRACTION92
2.0604-2.26770.23121360.17082459X-RAY DIFFRACTION92
2.2677-2.59580.23381300.18532459X-RAY DIFFRACTION91
2.5958-3.26990.21811190.19612443X-RAY DIFFRACTION89

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