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- PDB-6c8x: Wild-type HIV-1 protease in complex with a phenylboronic acid (P2... -

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Basic information

Entry
Database: PDB / ID: 6c8x
TitleWild-type HIV-1 protease in complex with a phenylboronic acid (P2') analog of darunavir
ComponentsProtease
KeywordsHYDROLASE/HYDROLASE INHIBITOR / HIV / Protease / Boronic Acid / Inhibitor / HYDROLASE-HYDROLASE INHIBITOR complex
Function / homology
Function and homology information


HIV-1 retropepsin / symbiont-mediated activation of host apoptosis / retroviral ribonuclease H / exoribonuclease H / exoribonuclease H activity / host multivesicular body / DNA integration / viral genome integration into host DNA / RNA-directed DNA polymerase / establishment of integrated proviral latency ...HIV-1 retropepsin / symbiont-mediated activation of host apoptosis / retroviral ribonuclease H / exoribonuclease H / exoribonuclease H activity / host multivesicular body / DNA integration / 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 / 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 / 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-BVR / Gag-Pol polyprotein / Protease
Similarity search - Component
Biological speciesHuman immunodeficiency virus 1
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.613 Å
AuthorsWindsor, I.W. / Raines, R.T. / Forest, K.T.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01 GM044783 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)T32 GM008349 United States
CitationJournal: J. Am. Chem. Soc. / Year: 2018
Title: Sub-picomolar Inhibition of HIV-1 Protease with a Boronic Acid.
Authors: Windsor, I.W. / Palte, M.J. / Lukesh 3rd., J.C. / Gold, B. / Forest, K.T. / Raines, R.T.
History
DepositionJan 25, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 5, 2018Provider: repository / Type: Initial release
Revision 1.1Jan 1, 2020Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.2Oct 4, 2023Group: Advisory / Data collection ...Advisory / 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 / pdbx_unobs_or_zero_occ_atoms
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)22,2206
Polymers21,4812
Non-polymers7384
Water3,387188
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4420 Å2
ΔGint-39 kcal/mol
Surface area9610 Å2
MethodPISA
Unit cell
Length a, b, c (Å)58.710, 86.203, 46.168
Angle α, β, γ (deg.)90.000, 90.000, 90.000
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: Q7K, L33I, L63I, C67A, C95A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human immunodeficiency virus 1 / Gene: pol / Plasmid: pET32b / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): DE3 Codon Plus / References: UniProt: Q5RZ08, UniProt: P03366*PLUS
#2: Chemical ChemComp-BVR / [4-[[(2~{R},3~{S})-3-[[(3~{a}~{S},4~{R},6~{a}~{R})-2,3,3~{a},4,5,6~{a}-hexahydrofuro[2,3-b]furan-4-yl]oxycarbonylamino]-2-oxidanyl-4-phenyl-butyl]-(2-methylpropyl)sulfamoyl]phenyl]-oxidanyl-oxidanylidene-boron


Mass: 575.459 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Formula: C27H36BN2O9S / Feature type: SUBJECT OF INVESTIGATION
#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: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 188 / 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: 54.77 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 7.4
Details: 2.0 mg/mL protease, 1.5 mg/mL ligand, 10% DMF, 100 mM Tris, pH 7.4, 200 mM sodium chloride

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-D / Wavelength: 0.97853 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Feb 12, 2015
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97853 Å / Relative weight: 1
ReflectionResolution: 1.6→27 Å / Num. obs: 30670 / % possible obs: 100 % / Redundancy: 14.3 % / Biso Wilson estimate: 15.5 Å2 / Rrim(I) all: 0.095 / Net I/σ(I): 38.3
Reflection shellResolution: 1.6→1.63 Å / Redundancy: 13.2 % / Mean I/σ(I) obs: 3.5 / Num. unique obs: 1507 / Rrim(I) all: 0.667 / % possible all: 100

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Phasing

PhasingMethod: molecular replacement
Phasing MR
Highest resolutionLowest resolution
Rotation1.61 Å24.77 Å
Translation1.61 Å24.77 Å

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Processing

Software
NameVersionClassification
PHENIXdev_2621refinement
HKL-2000data reduction
PHASER2.5.6phasing
PDB_EXTRACT3.24data extraction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 3NU3

3nu3


Resolution: 1.613→24.772 Å / SU ML: 0.14 / Cross valid method: THROUGHOUT / σ(F): 1.36 / Phase error: 18.2 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1967 1508 4.92 %
Rwork0.1735 29118 -
obs0.1747 30626 99.07 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 68.72 Å2 / Biso mean: 18.578 Å2 / Biso min: 6.66 Å2
Refinement stepCycle: final / Resolution: 1.613→24.772 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1512 0 88 190 1790
Biso mean--15.04 28 -
Num. residues----198
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0081721
X-RAY DIFFRACTIONf_angle_d1.0392362
X-RAY DIFFRACTIONf_chiral_restr0.069278
X-RAY DIFFRACTIONf_plane_restr0.007292
X-RAY DIFFRACTIONf_dihedral_angle_d8.8641378
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 11

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.6129-1.6650.20611220.19582361248390
1.665-1.72450.18321330.180426312764100
1.7245-1.79350.19971550.182226022757100
1.7935-1.87510.23091380.183826452783100
1.8751-1.97390.21591390.179726312770100
1.9739-2.09750.1951430.175626582801100
2.0975-2.25940.19841230.175526692792100
2.2594-2.48650.23041210.189926872808100
2.4865-2.84590.23521410.191426682809100
2.8459-3.58380.19491470.175527262873100
3.5838-24.77460.15891460.147428402986100

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