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- PDB-5wlo: a novel 13-ring macrocyclic HIV-1 protease inhibitors involving t... -

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Basic information

Entry
Database: PDB / ID: 5wlo
Titlea novel 13-ring macrocyclic HIV-1 protease inhibitors involving the P1'-P2' ligands
ComponentsProtease
Keywordshydrolase/hydrolase inhibitor / HIV protease / Macrocyclic inhibitors / P1'- P2' ligands / Drug resistance / HYDROLASE / hydrolase-hydrolase inhibitor complex
Function / homology
Function and homology information


exoribonuclease H activity / DNA integration / viral genome integration into host DNA / establishment of integrated proviral latency / RNA stem-loop binding / RNA-directed DNA polymerase activity / RNA-DNA hybrid ribonuclease activity / DNA recombination / aspartic-type endopeptidase activity / symbiont entry into host cell ...exoribonuclease H activity / DNA integration / viral genome integration into host DNA / establishment of integrated proviral latency / RNA stem-loop binding / RNA-directed DNA polymerase activity / RNA-DNA hybrid ribonuclease activity / DNA recombination / aspartic-type endopeptidase activity / symbiont entry into host cell / proteolysis / DNA binding / zinc ion binding
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. / 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 / 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) / Cathepsin D, subunit A; domain 1 / Acid Proteases / 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
ACETATE ION / Chem-GR7 / Protease / 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, 7items
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
National Institutes of Health/National Cancer Institute (NIH/NCI) United States
Ministry of Education, Culture, Sports, Science and Technology (Japan)a Grant-in-Aid for Scientific Research (Priority Areas) Japan
Ministry of Health,Labour and Welfare (Japan)a 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
National Institutes of Health/National Center for Research Resources (NIH/NCRR) United States
CitationJournal: Bioorg. Med. Chem. Lett. / Year: 2017
Title: Design, synthesis, X-ray studies, and biological evaluation of novel macrocyclic HIV-1 protease inhibitors involving the P1'-P2' ligands.
Authors: Ghosh, A.K. / Sean Fyvie, W. / Brindisi, M. / Steffey, M. / Agniswamy, J. / Wang, Y.F. / Aoki, M. / Amano, M. / Weber, I.T. / Mitsuya, H.
History
DepositionJul 27, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 11, 2017Provider: repository / Type: Initial release
Revision 1.1Oct 18, 2017Group: Author supporting evidence / Category: pdbx_audit_support
Revision 1.2Oct 25, 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 / 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.ptnr2_auth_seq_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)22,46311
Polymers21,4812
Non-polymers9829
Water3,441191
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5210 Å2
ΔGint-73 kcal/mol
Surface area9430 Å2
MethodPISA
Unit cell
Length a, b, c (Å)58.475, 86.034, 45.877
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 / Gene: pol / Plasmid: pET11a / Production host: Escherichia coli (E. coli) / Strain (production host): Bl21 (de3) / References: UniProt: Q5RZ08, UniProt: Q72498*PLUS

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Non-polymers , 6 types, 200 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.: 5 / Source method: obtained synthetically / Formula: Cl
#4: Chemical ChemComp-GR7 / (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl {(2S,3R)-3-hydroxy-4-[(7E)-13-methoxy-1,1-dioxo-1,4,5,6,9,11-hexahydro-10,1lambda~6~,2-benzoxathiazacyclotridecin-2(3H)-yl]-1-phenylbutan-2-yl}carbamate


Mass: 630.749 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C32H42N2O9S / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#6: Chemical ChemComp-ACT / ACETATE ION


Mass: 59.044 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H3O2
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 191 / 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: 2.69 Å3/Da / Density % sol: 54.21 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 4.4 / Details: 1.25 M NaCl, 0.1 M Acetate, pH 4.4 / PH range: 4.4

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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: Jun 28, 2017
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: 61214 / % possible obs: 98.9 % / Redundancy: 6 % / Rmerge(I) obs: 0.064 / Net I/σ(I): 26.6
Reflection shellResolution: 1.27→1.32 Å / Redundancy: 3.3 % / Rmerge(I) obs: 0.507 / Mean I/σ(I) obs: 2.4 / % possible all: 89.4

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Processing

Software
NameVersionClassification
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
SHELXL2014refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3I6O

3i6o


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
Rfree0.2054 3018 5 %RANDOM
Rwork0.1589 ---
all0.1612 ---
obs-61125 98.9 %-
Refine analyzeNum. disordered residues: 55 / Occupancy sum hydrogen: 0 / Occupancy sum non hydrogen: 1712.5
Refinement stepCycle: LAST / Resolution: 1.27→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1512 0 44 207 1763
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONs_bond_d0.0125
X-RAY DIFFRACTIONs_angle_d0.0327
X-RAY DIFFRACTIONs_similar_dist0
X-RAY DIFFRACTIONs_from_restr_planes0.0045
X-RAY DIFFRACTIONs_zero_chiral_vol0.0743
X-RAY DIFFRACTIONs_non_zero_chiral_vol0.4059
X-RAY DIFFRACTIONs_anti_bump_dis_restr0.0243
X-RAY DIFFRACTIONs_rigid_bond_adp_cmpnt0
X-RAY DIFFRACTIONs_similar_adp_cmpnt0.0551
X-RAY DIFFRACTIONs_approx_iso_adps0.0999

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