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- PDB-1ebk: Structural and kinetic analysis of drug resistant mutants of HIV-... -

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Basic information

Entry
Database: PDB / ID: 1ebk
TitleStructural and kinetic analysis of drug resistant mutants of HIV-1 protease
ComponentsHIV-1 PROTEASE
KeywordsHYDROLASE/HYDROLASE INHIBITOR / HIV-1 PROTEASE / 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 / DNA integration / host multivesicular body / 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 / DNA integration / host multivesicular body / viral genome integration into host DNA / RNA-directed DNA polymerase / establishment of integrated proviral latency / RNA stem-loop binding / viral penetration into host nucleus / 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 / aspartic-type endopeptidase activity / Hydrolases; Acting on ester bonds / DNA-directed DNA polymerase activity / symbiont-mediated suppression of host gene expression / viral translational frameshifting / lipid binding / symbiont entry into host cell / 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. / Retropepsin-like catalytic domain / Matrix protein, lentiviral and alpha-retroviral, N-terminal / Retroviral nucleocapsid Gag protein p24, C-terminal domain / Gag protein p24 C-terminal domain / RNase H type-1 domain profile. / Ribonuclease H domain / Retropepsins / Retroviral aspartyl protease / Aspartyl protease, retroviral-type family profile. / Peptidase A2A, retrovirus, catalytic / Retrovirus capsid, C-terminal / Reverse transcriptase domain / Reverse transcriptase (RNA-dependent DNA polymerase) / Reverse transcriptase (RT) catalytic domain profile. / Retroviral matrix protein / Cathepsin D, subunit A; domain 1 / Acid Proteases / Retrovirus capsid, N-terminal / zinc finger / Zinc knuckle / Zinc finger, CCHC-type superfamily / Zinc finger, CCHC-type / Zinc finger CCHC-type profile. / Aspartic peptidase, active site / Eukaryotic and viral aspartyl proteases active site. / Aspartic peptidase domain superfamily / Ribonuclease H 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 / Resolution: 2.06 Å
AuthorsMahalingam, B. / Louis, J.M. / Reed, C.C. / Adomat, J.M. / Krouse, J. / Wang, Y.F. / Harrison, R.W. / Weber, I.T.
CitationJournal: Eur.J.Biochem. / Year: 1999
Title: Structural and kinetic analysis of drug resistant mutants of HIV-1 protease.
Authors: Mahalingam, B. / Louis, J.M. / Reed, C.C. / Adomat, J.M. / Krouse, J. / Wang, Y.F. / Harrison, R.W. / Weber, I.T.
History
DepositionJan 24, 2000Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 26, 2000Provider: 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 4, 2017Group: Refinement description / Category: software
Revision 1.5Nov 3, 2021Group: Database references / Derived calculations
Category: database_2 / struct_ref_seq_dif ...database_2 / 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 / _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 1.6Feb 7, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
C: HIV-1 PROTEASE
D: HIV-1 PROTEASE
E: HIV-1 PROTEASE
F: HIV-1 PROTEASE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,5136
Polymers42,8464
Non-polymers1,6662
Water2,594144
1
C: HIV-1 PROTEASE
D: HIV-1 PROTEASE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,2563
Polymers21,4232
Non-polymers8331
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5060 Å2
ΔGint-30 kcal/mol
Surface area9160 Å2
MethodPISA
2
E: HIV-1 PROTEASE
F: HIV-1 PROTEASE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,2563
Polymers21,4232
Non-polymers8331
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5390 Å2
ΔGint-29 kcal/mol
Surface area9160 Å2
MethodPISA
Unit cell
Length a, b, c (Å)59.410, 61.950, 51.840
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number4
Space group name H-MP1211
DetailsThe biological assembly is a dimer consisting of chains C and D or chains E and F

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Components

#1: Protein
HIV-1 PROTEASE


Mass: 10711.611 Da / Num. of mol.: 4 / Fragment: FRAGMENT 69-167 / Mutation: Q7K, R8Q, L33I, L63I, C67A, C95A
Source method: isolated from a genetically manipulated source
Details: ENGINEERED MUTATIONS Q7K, R8Q, L33I, L63I, C67A, C95A STABILIZE THE PROTEASE FROM AUTOPROTEOLYSIS, WHILE RETAINING ACTIVITY SIMILAR TO WILD-TYPE HIV-1 PROTEASE
Source: (gene. exp.) Human immunodeficiency virus 1 / Production host: Escherichia coli (E. coli) / References: UniProt: P03366, 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.: 2 / 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


Mass: 18.015 Da / Num. of mol.: 144 / Source method: isolated from a natural source / Formula: H2O
Nonpolymer detailsPEPTIDE INHIBITOR 0Q4 HAS A REDUCED PEPTIDE (-CH2-NH) INSTEAD OF THE NORMAL PEPTIDE LINK (-CO-NH).
Sequence detailsENGINEERED MUTATIONS Q7K, R8Q, L33I, L63I, C67A, C95A STABILIZE THE PROTEASE FROM AUTOPROTEOLYSIS, ...ENGINEERED MUTATIONS Q7K, R8Q, L33I, L63I, C67A, C95A 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: 2.14 Å3/Da / Density % sol: 42.58 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop
Details: CITRATE/PHOSPHATE BUFFER 0.05M, DTT 10MM, DMSO 10%, SATURATED AMMONIUM SULPHATE (25-50%), PROTEIN 2-5 MG/ML, VAPOR DIFFUSION, HANGING DROP, temperature 298K
Crystal grow
*PLUS
Method: vapor diffusion / PH range low: 5.2 / PH range high: 4.7
Components of the solutions
*PLUS
IDConc.Common nameCrystal-IDSol-ID
14.5-8.0 mg/mlprotease1drop
220-55 mMsodium acetate1drop
366 mMsodium citrate1reservoir
4132 mMsodium phosphate1reservoir
530-36 %satammonium sulfate1reservoir

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Data collection

DiffractionMean temperature: 298 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RU200 / Wavelength: 1.54
DetectorType: RIGAKU RAXIS IIC / Detector: IMAGE PLATE
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionNum. obs: 19007 / % possible obs: 79.2 % / Rmerge(I) obs: 0.084

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Processing

SoftwareName: X-PLOR / Classification: refinement
RefinementResolution: 2.06→8 Å / Stereochemistry target values: Engh & Huber /
RfactorNum. reflection
Rfree0.306 -
Rwork0.192 -
obs-19007
Refinement stepCycle: LAST / Resolution: 2.06→8 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3016 0 118 144 3278
Software
*PLUS
Name: X-PLOR / Classification: refinement
Refinement
*PLUS
Solvent computation
*PLUS
Displacement parameters
*PLUS
Biso mean: 16.55 Å2
Refine LS restraints
*PLUS
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONx_bond_d0.013
X-RAY DIFFRACTIONx_angle_deg1.99
X-RAY DIFFRACTIONx_angle_d
X-RAY DIFFRACTIONx_dihedral_angle_deg26.23
X-RAY DIFFRACTIONx_dihedral_angle_d
X-RAY DIFFRACTIONx_improper_angle_deg1.56
X-RAY DIFFRACTIONx_improper_angle_d
X-RAY DIFFRACTIONx_mcbond_it
X-RAY DIFFRACTIONx_scbond_it
X-RAY DIFFRACTIONx_mcangle_it
X-RAY DIFFRACTIONx_scangle_it

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