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- PDB-6cdj: HIV-1 wild type protease with GRL-03314A, 6-5-5-ring fused umbrel... -

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Basic information

Entry
Database: PDB / ID: 6cdj
TitleHIV-1 wild type protease with GRL-03314A, 6-5-5-ring fused umbrella-like tetrahydropyranofuran as the P2-ligand, a cyclopropylaminobenzothiazole as the P2'-ligand and 3,5-difluorophenylmethyl as the P1-ligand
ComponentsProtease
KeywordsHYDROLASE/HYDROLASE inhibitor / aspartic acid protease / HIV-1 protease inhibitor of GRL-03314A / Umb-THF / antiviral / multidrug-resistant / synthesis / backbone binding / HYDROLASE / HYDROLASE-HYDROLASE inhibitor complex
Function / homology
Function and homology information


aspartic-type endopeptidase activity / proteolysis
Similarity search - Function
Retropepsin-like catalytic domain / Retropepsins / Retroviral aspartyl protease / Aspartyl protease, retroviral-type family profile. / Peptidase A2A, retrovirus, catalytic / Cathepsin D, subunit A; domain 1 / Acid Proteases / Aspartic peptidase, active site / Eukaryotic and viral aspartyl proteases active site. / Aspartic peptidase domain superfamily ...Retropepsin-like catalytic domain / Retropepsins / Retroviral aspartyl protease / Aspartyl protease, retroviral-type family profile. / Peptidase A2A, retrovirus, catalytic / Cathepsin D, subunit A; domain 1 / Acid Proteases / Aspartic peptidase, active site / Eukaryotic and viral aspartyl proteases active site. / Aspartic peptidase domain superfamily / Beta Barrel / Mainly Beta
Similarity search - Domain/homology
ACETATE ION / Chem-GR8 / Protease
Similarity search - Component
Biological speciesHuman immunodeficiency virus 1
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.13 Å
AuthorsWang, Y.-F. / Agniswamy, J. / Weber, I.T.
Funding support United States, Japan, 6items
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)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 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
CitationJournal: J. Med. Chem. / Year: 2018
Title: Design and Synthesis of Highly Potent HIV-1 Protease Inhibitors Containing Tricyclic Fused Ring Systems as Novel P2 Ligands: Structure-Activity Studies, Biological and X-ray Structural Analysis.
Authors: Ghosh, A.K. / R Nyalapatla, P. / Kovela, S. / Rao, K.V. / Brindisi, M. / Osswald, H.L. / Amano, M. / Aoki, M. / Agniswamy, J. / Wang, Y.F. / Weber, I.T. / Mitsuya, H.
History
DepositionFeb 8, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 30, 2018Provider: repository / Type: Initial release
Revision 1.1Jun 6, 2018Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Feb 20, 2019Group: Author supporting evidence / Data collection / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
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)22,54210
Polymers21,4812
Non-polymers1,0608
Water3,891216
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5070 Å2
ΔGint-60 kcal/mol
Surface area9650 Å2
MethodPISA
Unit cell
Length a, b, c (Å)58.959, 86.077, 46.157
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 BL21(DE3) (bacteria) / Strain (production host): Bl21(de3) / References: UniProt: Q5RZ08

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Non-polymers , 6 types, 224 molecules

#2: Chemical ChemComp-GR8 / (2aS,4R,4aS,7aS,7bS)-octahydro-2H-1,7-dioxacyclopenta[cd]inden-4-yl [(2S,3R)-4-[{[2-(cyclopropylamino)-1,3-benzothiazol-6-yl]sulfonyl}(2-methylpropyl)amino]-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl]carbamate


Mass: 720.847 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C34H42F2N4O7S2
#3: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / 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.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#6: Chemical ChemComp-ACT / ACETATE ION


Mass: 59.044 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H3O2
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 216 / 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: 2.73 Å3/Da / Density % sol: 54.95 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 5.5 / Details: 0.95M NaCl, 0.1M Sodium Acetate pH 5.5 / 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: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Oct 23, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.13→50 Å / Num. obs: 80076 / % possible obs: 90.4 % / Redundancy: 7.1 % / Rmerge(I) obs: 0.078 / Net I/σ(I): 20.8
Reflection shellResolution: 1.13→1.17 Å / Redundancy: 2.5 % / Rmerge(I) obs: 0.345 / Mean I/σ(I) obs: 3 / Num. unique obs: 4350 / % possible all: 49.9

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Processing

Software
NameClassification
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
SHELXL-97refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3NU3

3nu3


Resolution: 1.13→50 Å / Cross valid method: FREE R-VALUE / σ(F): 0
Details: ANISOTROPIC REFINEMENT REDUCED FREE R (NO CUTOFF) BY ?
RfactorNum. reflection% reflectionSelection details
Rfree0.1731 3898 5 %RANDOM
Rwork0.1425 ---
all0.144 80017 --
obs0.144 80017 90.3 %-
Refine analyzeNum. disordered residues: 80 / Occupancy sum hydrogen: 1641 / Occupancy sum non hydrogen: 1738.7
Refinement stepCycle: LAST / Resolution: 1.13→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1512 0 49 238 1799
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONs_bond_d0.0138
X-RAY DIFFRACTIONs_angle_d0.033
X-RAY DIFFRACTIONs_similar_dist0
X-RAY DIFFRACTIONs_from_restr_planes0.4114
X-RAY DIFFRACTIONs_zero_chiral_vol0.0769
X-RAY DIFFRACTIONs_non_zero_chiral_vol0.0884
X-RAY DIFFRACTIONs_anti_bump_dis_restr0.0315
X-RAY DIFFRACTIONs_rigid_bond_adp_cmpnt0
X-RAY DIFFRACTIONs_similar_adp_cmpnt0.0504
X-RAY DIFFRACTIONs_approx_iso_adps0.1002

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