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- PDB-6dv0: HIV-1 wild type protease with GRL-02815A, a thiochroman heterocyc... -

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Basic information

Entry
Database: PDB / ID: 6dv0
TitleHIV-1 wild type protease with GRL-02815A, a thiochroman heterocycle with (S)-Boc-amine functionality as the P2 ligand
ComponentsProtease
KeywordsHYDROLASE / ANTIVIRAL PROTEIN / aspartic acid protease / HIV-1 protease inhibitor of GRL-02815A / thiochroman / P2 ligand / drug resistance / design and synthesis
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-GA8 / Gag-Pol polyprotein / Protease
Similarity search - Component
Biological speciesHuman immunodeficiency virus 1
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.2 Å
AuthorsWang, Y.-F. / Agniswamy, J. / Weber, I.T.
Funding support United States, Japan, 5items
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
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: Eur J Med Chem / Year: 2018
Title: Design, synthesis, and X-ray studies of potent HIV-1 protease inhibitors incorporating aminothiochromane and aminotetrahydronaphthalene carboxamide derivatives as the P2 ligands.
Authors: Ghosh, A.K. / Jadhav, R.D. / Simpson, H. / Kovela, S. / Osswald, H. / Agniswamy, J. / Wang, Y.F. / Hattori, S.I. / Weber, I.T. / Mitsuya, H.
History
DepositionJun 22, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 31, 2018Provider: repository / Type: Initial release
Revision 1.1Dec 4, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.2Oct 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.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)22,3657
Polymers21,4812
Non-polymers8845
Water3,711206
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4700 Å2
ΔGint-50 kcal/mol
Surface area9640 Å2
MethodPISA
Unit cell
Length a, b, c (Å)58.719, 86.109, 46.193
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 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: Q5RZ08, UniProt: P04585*PLUS

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Non-polymers , 5 types, 211 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.: 2 / Source method: obtained synthetically / Formula: Cl
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#5: Chemical ChemComp-GA8 / tert-butyl [(4S)-6-{[(2S,3R)-3-hydroxy-4-{[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino}-1-phenylbutan-2-yl]carbamoyl}-3,4-dihydro-2H-1-benzothiopyran-4-yl]carbamate


Mass: 697.904 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C36H47N3O7S2
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 206 / 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: 2.72 Å3/Da / Density % sol: 54.75 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 6.4 / Details: 0.90M NaCl, 0.1M Sodium Cacodylate pH 6.4 / PH range: 6.4

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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: 1.2→50 Å / Num. obs: 67382 / % possible obs: 91.1 % / Redundancy: 6.9 % / Rmerge(I) obs: 0.085 / Net I/σ(I): 20.1
Reflection shellResolution: 1.2→1.24 Å / Redundancy: 2.1 % / Rmerge(I) obs: 0.37 / Mean I/σ(I) obs: 3.4 / Num. unique obs: 3797 / % possible all: 52.1

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Processing

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

3nu3


Resolution: 1.2→50 Å / Cross valid method: FREE R-VALUE / σ(F): 0
Details: ANISOTROPIC REFINEMENT REDUCED FREE R (NO CUTOFF) BY ?
RfactorNum. reflection% reflectionSelection details
Rfree0.1857 3298 5 %RANDOM
Rwork0.1498 ---
all0.1516 67328 --
obs-67328 91.1 %-
Refine analyzeNum. disordered residues: 55 / Occupancy sum hydrogen: 0 / Occupancy sum non hydrogen: 1734.1
Refinement stepCycle: LAST / Resolution: 1.2→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1512 0 48 215 1775
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONs_bond_d0.0131
X-RAY DIFFRACTIONs_angle_d0.0317
X-RAY DIFFRACTIONs_similar_dist0
X-RAY DIFFRACTIONs_from_restr_planes0.0047
X-RAY DIFFRACTIONs_zero_chiral_vol0.0747
X-RAY DIFFRACTIONs_non_zero_chiral_vol0.0818
X-RAY DIFFRACTIONs_anti_bump_dis_restr0.0292
X-RAY DIFFRACTIONs_rigid_bond_adp_cmpnt0
X-RAY DIFFRACTIONs_similar_adp_cmpnt0.049
X-RAY DIFFRACTIONs_approx_iso_adps0.1034

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