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- PDB-8dch: Crystal Structure of a highly resistant HIV-1 protease Clinical i... -

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Basic information

Entry
Database: PDB / ID: 8dch
TitleCrystal Structure of a highly resistant HIV-1 protease Clinical isolate PR10x with GRL-0519 (tris-tetrahydrofuran as P2 ligand)
ComponentsProtease
KeywordsVIRAL PROTEIN / HYDROLASE/INHIBITOR / HIV/AIDS / HIV protease / drug resistant clinical mutant / evolution of drug resistance / distal mutations / HYDROLASE-INHIBITOR complex
Function / homology
Function and homology information


HIV-1 retropepsin / : / retroviral ribonuclease H / exoribonuclease H / : / exoribonuclease H activity / host multivesicular body / DNA integration / RNA-directed DNA polymerase / viral genome integration into host DNA ...HIV-1 retropepsin / : / retroviral ribonuclease H / exoribonuclease H / : / exoribonuclease H activity / host multivesicular body / DNA integration / RNA-directed DNA polymerase / viral genome integration into host DNA / viral penetration into host nucleus / establishment of integrated proviral latency / RNA-directed DNA polymerase activity / Transferases; Transferring phosphorus-containing groups; Nucleotidyltransferases / RNA-DNA hybrid ribonuclease activity / viral nucleocapsid / DNA recombination / Hydrolases; Acting on ester bonds / DNA-directed DNA polymerase / aspartic-type endopeptidase activity / DNA-directed DNA polymerase activity / symbiont entry into host cell / symbiont-mediated suppression of host gene expression / lipid binding / host cell nucleus / host cell plasma membrane / virion membrane / structural molecule activity / proteolysis / DNA binding / RNA 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. / Retroviral nucleocapsid Gag protein p24, C-terminal domain / Gag protein p24 C-terminal domain / Retropepsin-like catalytic domain / Matrix protein, lentiviral and alpha-retroviral, N-terminal / Ribonuclease H domain / RNase H type-1 domain profile. / Reverse transcriptase (RNA-dependent DNA polymerase) / Reverse transcriptase domain / Reverse transcriptase (RT) catalytic domain profile. / Retropepsins / Retroviral aspartyl protease / Aspartyl protease, retroviral-type family profile. / Peptidase A2A, retrovirus, catalytic / Retrovirus capsid, C-terminal / Retroviral matrix protein / Retrovirus capsid, N-terminal / zinc finger / Zinc knuckle / Zinc finger, CCHC-type superfamily / Zinc finger, CCHC-type / Zinc finger CCHC-type profile. / Ribonuclease H superfamily / Aspartic peptidase, active site / Eukaryotic and viral aspartyl proteases active site. / Aspartic peptidase domain superfamily / Ribonuclease H-like superfamily / Reverse transcriptase/Diguanylate cyclase domain / DNA/RNA polymerase superfamily
Similarity search - Domain/homology
Chem-G52 / Gag-Pol polyprotein
Similarity search - Component
Biological speciesHuman immunodeficiency virus 1
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.25 Å
AuthorsWong-Sam, A.E. / Wang, Y.-F. / Weber, I.T.
Funding support United States, 4items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)AI150461 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)AI150466 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)an NIH diversity supplement United States
Department of Energy (DOE, United States)W-31-109-Eng-38 United States
CitationJournal: J.Mol.Graph.Model. / Year: 2022
Title: HIV-1 protease with 10 lopinavir and darunavir resistance mutations exhibits altered inhibition, structural rearrangements and extreme dynamics.
Authors: Wong-Sam, A. / Wang, Y.F. / Kneller, D.W. / Kovalevsky, A.Y. / Ghosh, A.K. / Harrison, R.W. / Weber, I.T.
History
DepositionJun 16, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 5, 2022Provider: repository / Type: Initial release
Revision 1.1Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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)22,3376
Polymers21,5692
Non-polymers7684
Water3,837213
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4420 Å2
ΔGint-41 kcal/mol
Surface area9510 Å2
MethodPISA
Unit cell
Length a, b, c (Å)56.659, 56.659, 78.155
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number76
Space group name H-MP41

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Components

#1: Protein Protease / / PR / Retropepsin


Mass: 10784.560 Da / Num. of mol.: 2
Mutation: Q7K, L10F, I13V, L19I, K20T, V32I, L33I, E35N, M36I, M46I, G48Q, I54L, L63P, C67E, A71V, T74S, L76V, I84V, L89V, L90M, T91S, I93L, C95A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human immunodeficiency virus 1 / Strain: Clinical isolate PR76Vmx / Gene: gag-pol / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P03367, HIV-1 retropepsin
#2: Chemical ChemComp-G52 / (3R,3aS,3bR,6aS,7aS)-octahydrodifuro[2,3-b:3',2'-d]furan-3-yl [(1S,2R)-1-benzyl-2-hydroxy-3-{[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino}propyl]carbamate


Mass: 604.712 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C30H40N2O9S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-CL / CHLORIDE ION / Chloride


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 / Glycerol


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 213 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.5 Å3/Da / Density % sol: 57.7 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 5.2
Details: Hanging-drop vapor diffusion using equal volumes of protein stock (3.9 mg/mL) and well reservoir solution. Cryoprotected in 30% glycerol. Complex on ice at 1:8 ratio of PR to PI, ...Details: Hanging-drop vapor diffusion using equal volumes of protein stock (3.9 mg/mL) and well reservoir solution. Cryoprotected in 30% glycerol. Complex on ice at 1:8 ratio of PR to PI, crystallized in 1 M NaCl and 0.1 M sodium acetate pH 5.2

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
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: 1.25→50 Å / Num. obs: 67583 / % possible obs: 99.4 % / Redundancy: 6.8 % / Rmerge(I) obs: 0.08 / Rpim(I) all: 0.033 / Rrim(I) all: 0.086 / Χ2: 0.999 / Net I/σ(I): 20.7 / Num. measured all: 458139
Reflection shellResolution: 1.25→1.29 Å / Redundancy: 3.3 % / Rmerge(I) obs: 0.389 / Mean I/σ(I) obs: 3.1 / Num. unique obs: 6718 / CC1/2: 0.991 / Rpim(I) all: 0.03 / Rrim(I) all: 0.078 / Χ2: 1.003 / % possible all: 97

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Phasing

PhasingMethod: molecular replacement
Phasing MRR rigid body: 0.659
Highest resolutionLowest resolution
Rotation28.33 Å1.54 Å

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Processing

Software
NameVersionClassification
HKL-2000data scaling
MOLREPphasing
SHELX1997refinement
PDB_EXTRACT3.27data extraction
HKL-2000data reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3NU3

3nu3


Resolution: 1.25→50 Å / Cross valid method: FREE R-VALUE / σ(F): 0 / Stereochemistry target values: ENGH AND HUBER
Details: ANISOTROPIC REFINEMENT REDUCED FREE R (NO CUTOFF) BY ?
RfactorNum. reflection% reflectionSelection details
Rfree0.1864 3385 5 %RANDOM
Rwork0.1457 ---
all0.1479 67583 --
obs0.1479 67540 99.4 %-
Solvent computationSolvent model: MOEWS & KRETSINGER, J.MOL.BIOL.91(1973)201-228
Displacement parametersBiso max: 68.63 Å2 / Biso mean: 20.3406 Å2 / Biso min: 6.68 Å2
Refinement stepCycle: final / Resolution: 1.25→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1522 0 92 213 1827
Biso mean--14.87 30.13 -
Num. residues----198
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONs_bond_d0.013
X-RAY DIFFRACTIONs_angle_d0.035
X-RAY DIFFRACTIONs_similar_dist0
X-RAY DIFFRACTIONs_from_restr_planes0.034
X-RAY DIFFRACTIONs_zero_chiral_vol0.08
X-RAY DIFFRACTIONs_non_zero_chiral_vol0.086
X-RAY DIFFRACTIONs_anti_bump_dis_restr0.02
X-RAY DIFFRACTIONs_rigid_bond_adp_cmpnt0.005
X-RAY DIFFRACTIONs_similar_adp_cmpnt0.052
X-RAY DIFFRACTIONs_approx_iso_adps0.092

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