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- PDB-6e7j: HIV-1 wild type protease with GRL-042-17A, 3-phenylhexahydro-2h-c... -

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Basic information

Entry
Database: PDB / ID: 6e7j
TitleHIV-1 wild type protease with GRL-042-17A, 3-phenylhexahydro-2h-cyclopenta[d]oxazol-2-one with a bicyclic oxazolidinone scaffold as the P2 ligand
ComponentsProtease
KeywordsHYDROLASE/HYDROLASE INHIBITOR / ANTIVIRAL / HIV-1 PROTEASE INHIBITOR OF GRL-042-17A / P2 LIGAND / MULTIDRUG-RESISTANT / OXAZOLIDINONE / VIRAL PROTEIN / 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-HWY / Gag-Pol polyprotein / Protease
Similarity search - Component
Biological speciesHuman immunodeficiency virus 1
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.3 Å
AuthorsWang, Y.-F. / Agniswamy, J. / Weber, I.T.
Funding support United States, Japan, 7items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)GM53386 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)GM62920 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)the Intramural Research Program of the Center for Cancer Research United States
Department of Energy (DOE, United States)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
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
CitationJournal: J. Med. Chem. / Year: 2018
Title: Design and Synthesis of Potent HIV-1 Protease Inhibitors Containing Bicyclic Oxazolidinone Scaffold as the P2 Ligands: Structure-Activity Studies and Biological and X-ray Structural Studies.
Authors: Ghosh, A.K. / Williams, J.N. / Ho, R.Y. / Simpson, H.M. / Hattori, S.I. / Hayashi, H. / Agniswamy, J. / Wang, Y.F. / Weber, I.T. / Mitsuya, H.
History
DepositionJul 26, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 7, 2018Provider: repository / Type: Initial release
Revision 1.1Nov 21, 2018Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Jul 17, 2019Group: Data collection / Refinement description / Category: software
Item: _software.classification / _software.name / _software.version
Revision 1.3Dec 4, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.4Oct 11, 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 / 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)22,3219
Polymers21,4812
Non-polymers8407
Water2,792155
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4890 Å2
ΔGint-77 kcal/mol
Surface area9460 Å2
MethodPISA
Unit cell
Length a, b, c (Å)59.793, 86.043, 45.875
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP21212

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Components

#1: Protein Protease


Mass: 10740.677 Da / Num. of mol.: 2 / Mutation: K7Q, I33L, I63L, A67C, A95C
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: P04585*PLUS
#2: Chemical ChemComp-HWY / (3aS,5R,6aR)-2-oxo-3-phenylhexahydro-2H-cyclopenta[d][1,3]oxazol-5-yl [(2S,3R)-3-hydroxy-4-{[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino}-1-phenylbutan-2-yl]carbamate


Mass: 651.770 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C34H41N3O8S
#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.: 4 / Source method: obtained synthetically / Formula: Cl
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 155 / 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: 2.75 Å3/Da / Density % sol: 55.22 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 5.5
Details: 1.4M NACL, 0.1M SODIUM ACETATE PH 5.5, VAPOR DIFFUSION, HANGING DROP, TEMPERATURE 298K
PH range: 5.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-ID / Wavelength: 1 Å
DetectorType: RAYONIX MX300HE / Detector: CCD / Date: Oct 25, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.3→50 Å / Num. obs: 54309 / % possible obs: 92.1 % / Redundancy: 6.7 % / Rmerge(I) obs: 0.082 / Net I/σ(I): 19.7
Reflection shellResolution: 1.3→1.35 Å / Redundancy: 2.4 % / Rmerge(I) obs: 0.506 / Mean I/σ(I) obs: 2.1 / Num. unique obs: 3063 / % possible all: 53

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Processing

Software
NameVersionClassification
REFMAC5.8.0222refinement
HKL-2000data scaling
PHASERphasing
SHELXL2014refinement
HKL-2000data reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3NU3

3nu3


Resolution: 1.3→49.1 Å / Cor.coef. Fo:Fc: 0.975 / Cor.coef. Fo:Fc free: 0.959 / SU B: 2.209 / SU ML: 0.039 / Cross valid method: THROUGHOUT / ESU R: 0.045 / ESU R Free: 0.046 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.18234 2772 5.1 %RANDOM
Rwork0.14792 ---
obs0.14971 51484 92.01 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 22.151 Å2
Baniso -1Baniso -2Baniso -3
1--1.62 Å20 Å2-0 Å2
2--1.13 Å20 Å2
3---0.5 Å2
Refinement stepCycle: LAST / Resolution: 1.3→49.1 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1512 0 52 155 1719
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0180.0141679
X-RAY DIFFRACTIONr_bond_other_d0.0020.0171693
X-RAY DIFFRACTIONr_angle_refined_deg1.9471.6992298
X-RAY DIFFRACTIONr_angle_other_deg1.0361.6583971
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.3925223
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.09322.61565
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.68715318
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.827159
X-RAY DIFFRACTIONr_chiral_restr0.1360.2243
X-RAY DIFFRACTIONr_gen_planes_refined0.0120.021822
X-RAY DIFFRACTIONr_gen_planes_other0.0040.02279
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_it2.4691.842818
X-RAY DIFFRACTIONr_mcbond_other2.4341.839817
X-RAY DIFFRACTIONr_mcangle_it2.9542.7761026
X-RAY DIFFRACTIONr_mcangle_other2.9542.7771027
X-RAY DIFFRACTIONr_scbond_it4.8572.377861
X-RAY DIFFRACTIONr_scbond_other4.8542.376862
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other4.9863.3461259
X-RAY DIFFRACTIONr_long_range_B_refined5.02922.4671692
X-RAY DIFFRACTIONr_long_range_B_other5.02922.1441664
X-RAY DIFFRACTIONr_rigid_bond_restr5.60933372
X-RAY DIFFRACTIONr_sphericity_free23.0335128
X-RAY DIFFRACTIONr_sphericity_bonded21.753361
LS refinement shellResolution: 1.3→1.334 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.257 116 -
Rwork0.251 1972 -
obs--49.06 %

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