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- PDB-1k2b: Combining Mutations in HIV-1 Protease to Understand Mechanisms of... -

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Basic information

Entry
Database: PDB / ID: 1k2b
TitleCombining Mutations in HIV-1 Protease to Understand Mechanisms of Resistance
ComponentsPROTEASE RETROPEPSIN
KeywordsHYDROLASE/HYDROLASE INHIBITOR / HIV-1 PROTEASE / HYDROLASE-HYDROLASE INHIBITOR COMPLEX
Function / homology
Function and homology information


RNA stem-loop binding / host cell / 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 ...RNA stem-loop binding / host cell / 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 / RNA-DNA hybrid ribonuclease activity / Transferases; Transferring phosphorus-containing groups; Nucleotidyltransferases / symbiont-mediated suppression of host gene expression / 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 / lipid binding / host cell nucleus / host cell plasma membrane / virion membrane / structural molecule activity / 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. / 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 / 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
N-[(2R)-2-({N~5~-[amino(iminio)methyl]-L-ornithyl-L-valyl}amino)-4-methylpentyl]-L-phenylalanyl-L-alpha-glutamyl- L-alanyl-L-norleucinamide / Chem-0Q4 / Gag-Pol polyprotein
Similarity search - Component
Biological speciesHuman immunodeficiency virus 1
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.7 Å
AuthorsMahalingam, B. / Boross, P. / Wang, Y.-F. / Louis, J.M. / Fischer, C. / Tozser, J. / W Harrison, R. / Weber, I.T.
CitationJournal: Proteins / Year: 2002
Title: Combining mutations in HIV-1 protease to understand mechanisms of resistance.
Authors: Mahalingam, B. / Boross, P. / Wang, Y.F. / Louis, J.M. / Fischer, C.C. / Tozser, J. / Harrison, R.W. / Weber, I.T.
History
DepositionSep 26, 2001Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 10, 2002Provider: repository / Type: Initial release
Revision 1.1Apr 27, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Atomic model / Database references ...Atomic model / Database references / Derived calculations / Non-polymer description / Structure summary / Version format compliance
Revision 1.3Dec 12, 2012Group: Other
Revision 1.4Oct 27, 2021Group: Database references / Derived calculations / Refinement description
Category: database_2 / software ...database_2 / software / struct_ref_seq_dif / struct_sheet / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _software.classification / _software.name / _struct_ref_seq_dif.details / _struct_sheet.number_strands / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.5Aug 16, 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 RETROPEPSIN
B: PROTEASE RETROPEPSIN
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,3523
Polymers21,5192
Non-polymers8331
Water2,306128
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5360 Å2
ΔGint-30 kcal/mol
Surface area9120 Å2
MethodPISA
Unit cell
Length a, b, c (Å)50.759, 57.541, 60.841
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein PROTEASE RETROPEPSIN / Retropepsin / PR


Mass: 10759.699 Da / Num. of mol.: 2 / Mutation: Q7K, l33I, L63I, C67A, C95A, N88D, L90M
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human immunodeficiency virus 1 / Genus: Lentivirus / Production host: Escherichia coli (E. coli) / References: UniProt: P04587, HIV-1 retropepsin
#2: Chemical ChemComp-0Q4 / N-[(2R)-2-({N~5~-[amino(iminio)methyl]-L-ornithyl-L-valyl}amino)-4-methylpentyl]-L-phenylalanyl-L-alpha-glutamyl-L-alanyl-L-norleucinamide / Inhibitor analogues of CA-p2


Type: peptide-like, Peptide-like / Class: Inhibitor / Mass: 833.053 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C40H70N11O8
References: N-[(2R)-2-({N~5~-[amino(iminio)methyl]-L-ornithyl-L-valyl}amino)-4-methylpentyl]-L-phenylalanyl-L-alpha-glutamyl- L-alanyl-L-norleucinamide
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 128 / Source method: isolated from a natural source / Formula: H2O
Nonpolymer detailsTHE INHIBITOR 0Q4 WAS CHEMICALLY SYNTHESIZED AND IS ANALOGOUS TO THE CA-P2 PROCESSING SITE ...THE INHIBITOR 0Q4 WAS CHEMICALLY SYNTHESIZED AND IS ANALOGOUS TO THE CA-P2 PROCESSING SITE INHIBITOR IN HIV-1 IT HAS A REDUCED PEPTIDE (-CH2-NH) INSTEAD OF THE NORMAL PEPTIDE LINK (-CO-NH).
Sequence detailsMUTATIONS Q7K, L33I, L63I, C67A, C95A, HAVE BEEN MADE TO STABILIZE THE PROTEASE FROM ...MUTATIONS Q7K, L33I, L63I, C67A, C95A, HAVE BEEN MADE TO STABILIZE THE PROTEASE FROM AUTOPROTEOLYSIS, WHILE RETAINING ACTIVITY SIMILAR TO WILD-TYPE HIV-1 PROTEASE

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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: 1.99 Å3/Da / Density % sol: 38.08 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop
Details: 20-50% Saturated Ammonium Sulphate, 10% DMSO, 0.25M citrate/0.5M phosphate buffer, VAPOR DIFFUSION, HANGING DROP, temperature 298K
Crystal grow
*PLUS
PH range low: 6.5 / PH range high: 5
Components of the solutions
*PLUS
IDConc.Common nameCrystal-IDSol-IDDetails
10.25 Mcitrate1reservoir
20.5 Mphosphate1reservoirpH5-6.5
310 %DMSO1reservoir
410 mMdithiothreitol1reservoir
520-50 %satammonium sulfate1reservoir
62-10 mg/mlprotein1drop

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Data collection

DiffractionMean temperature: 90 K
Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X12B / Wavelength: 1.037 Å
DetectorType: ADSC QUANTUM 4 / Detector: CCD / Date: Oct 8, 1999
RadiationMonochromator: Double-crystal, fixed-exit Si-III / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.037 Å / Relative weight: 1
ReflectionResolution: 1.7→25 Å / Num. all: 20000 / Num. obs: 20000 / % possible obs: 99 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2 / Redundancy: 4.1 % / Rmerge(I) obs: 0.042 / Net I/σ(I): 10.8
Reflection shellResolution: 1.7→1.76 Å / Rmerge(I) obs: 0.248 / Mean I/σ(I) obs: 5.1 / Num. unique all: 1958 / % possible all: 98.4
Reflection
*PLUS
Lowest resolution: 8 Å / % possible obs: 99 % / Rmerge(I) obs: 0.042
Reflection shell
*PLUS
Rmerge(I) obs: 0.248

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Processing

Software
NameClassification
AMoREphasing
X-PLORrefinement
Adxvdata processing
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1DAZ

1daz


Resolution: 1.7→8 Å / Isotropic thermal model: Isotropic / Cross valid method: FREE R / σ(F): 2 / Stereochemistry target values: ENGH AND HUBER
RfactorNum. reflectionSelection details
Rfree0.278 1972 RANDOM
Rwork0.215 --
obs-19780 -
Refinement stepCycle: LAST / Resolution: 1.7→8 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1512 0 59 128 1699
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONx_bond_d0.011
X-RAY DIFFRACTIONx_angle_d2.183
X-RAY DIFFRACTIONx_dihedral_angle_d25.523
X-RAY DIFFRACTIONx_improper_angle_d1.446
LS refinement shellResolution: 1.7→1.76 Å
RfactorNum. reflection
Rfree0.3784 183
Rwork0.3196 -
obs-1886
Refinement
*PLUS
Rfactor Rfree: 0.275 / Rfactor Rwork: 0.216
Solvent computation
*PLUS
Displacement parameters
*PLUS
Refine LS restraints
*PLUS
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONx_angle_d
X-RAY DIFFRACTIONx_angle_deg2.183
X-RAY DIFFRACTIONx_dihedral_angle_d
X-RAY DIFFRACTIONx_dihedral_angle_deg25.523
X-RAY DIFFRACTIONx_improper_angle_d
X-RAY DIFFRACTIONx_improper_angle_deg1.446
X-RAY DIFFRACTIONx_bond_d0.011
LS refinement shell
*PLUS
Highest resolution: 1.7 Å / Rfactor Rfree: 0.3784 / Rfactor Rwork: 0.3196

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