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- PDB-1n49: Viability of a Drug-Resistant HIV-1 Protease Variant: Structural ... -

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Basic information

Entry
Database: PDB / ID: 1n49
TitleViability of a Drug-Resistant HIV-1 Protease Variant: Structural Insights for Better Anti-Viral Therapy
ComponentsProtease
KeywordsHYDROLASE/HYDROLASE INHIBITOR / HIV-1 protease / drug resistance / substrate recognition / inhibitor binding / HYDROLASE / 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
RITONAVIR / RITONAVIR / Gag-Pol polyprotein
Similarity search - Component
Biological speciesHuman immunodeficiency virus 1
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.2 Å
AuthorsPrabu-Jeyabalan, M. / Nalivaika, E.A. / King, N.M. / Schiffer, C.A.
Citation
Journal: J.VIROL. / Year: 2003
Title: Viability of a Drug-Resistant Human Immunodeficiency Virus Type 1 Protease Variant: Structural Insights for Better Antiviral Therapy
Authors: Prabu-Jeyabalan, M. / Nalivaika, E.A. / King, N.M. / Schiffer, C.A.
#1: Journal: J.Mol.Biol. / Year: 2000
Title: How does a symmetric dimer recognize an asymmetric substrate? a substrate complex of HIV-1 protease
Authors: Prabu-Jeyabalan, M. / Nalivaika, E. / Schiffer, C.A.
#2: Journal: Structure / Year: 2002
Title: Substrate shape determines specificity of recognition for HIV-1 protease: analysis of crystal structures of six substrate complexes
Authors: Prabu-Jeyabalan, M. / Nalivaika, E. / Schiffer, C.A.
#3: Journal: Protein Sci. / Year: 2002
Title: Lack of synergy for inhibitors targeting a multi-drug resistant HIV-1 protease
Authors: King, N.M. / Melnick, L. / Prabu-Jeyabalan, M. / Nalivaika, E.A. / Yang, S.S. / Gao, Y. / Nie, X. / Zepp, C. / Heefner, D.L. / Schiffer, C.A.
#4: Journal: Proc.Natl.Acad.Sci.USA / Year: 1995
Title: ABT-538 Is a Potent Inhibitor of Human Immunodeficiency Virus Protease and has High Oral Bioavailability in Humans
Authors: Kempf, D.J. / Marsh, K.C. / Denissen, J.F. / McDonald, E. / Vasavanonda, S. / Flentge, C.A. / Green, B.E. / Fino, L. / Park, C.H. / Kong, X. / Wideburg, N.E. / Saldivar, A. / Ruiz, L. / ...Authors: Kempf, D.J. / Marsh, K.C. / Denissen, J.F. / McDonald, E. / Vasavanonda, S. / Flentge, C.A. / Green, B.E. / Fino, L. / Park, C.H. / Kong, X. / Wideburg, N.E. / Saldivar, A. / Ruiz, L. / Kati, W.M. / Sham, H.L. / Robins, T. / Stewart, K.D. / Hsu, A. / Plattner, J.J. / Leonard, J.M. / Norbeck, D.W.
History
DepositionOct 30, 2002Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 7, 2003Provider: repository / Type: Initial release
Revision 1.1Apr 28, 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 1.3Feb 27, 2013Group: Other
Revision 1.4Oct 11, 2017Group: Refinement description / Category: software
Revision 1.5Oct 27, 2021Group: Database references / Derived calculations / Category: database_2 / struct_ref_seq_dif / 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_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.6Feb 14, 2024Group: 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
C: Protease
D: Protease
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,5336
Polymers43,0914
Non-polymers1,4422
Water50428
1
A: Protease
B: Protease
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,2663
Polymers21,5452
Non-polymers7211
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4970 Å2
ΔGint-42 kcal/mol
Surface area8740 Å2
MethodPISA
2
C: Protease
D: Protease
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,2663
Polymers21,5452
Non-polymers7211
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5030 Å2
ΔGint-39 kcal/mol
Surface area8740 Å2
MethodPISA
Unit cell
Length a, b, c (Å)51.620, 61.350, 59.040
Angle α, β, γ (deg.)90.00, 81.20, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein
Protease / Retropepsin


Mass: 10772.724 Da / Num. of mol.: 4 / Mutation: Q7K, D25N, V82A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human immunodeficiency virus 1 / Genus: Lentivirus / Gene: POL / Plasmid: pEN18 / Production host: Escherichia coli (E. coli) / Strain (production host): TAP106 / References: UniProt: P03369, HIV-1 retropepsin
#2: Chemical ChemComp-RIT / RITONAVIR / A-84538


Type: peptide-like, Peptide-like / Class: Inhibitor / Mass: 720.944 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C37H48N6O5S2 / References: RITONAVIR
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 28 / 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: 2.14 Å3/Da / Density % sol: 42.59 %
Crystal growMethod: vapor diffusion, hanging drop / pH: 6.2
Details: sodium phosphate, sodium citrate, ammonium sulphate, pH 6.2, VAPOR DIFFUSION, HANGING DROP
Crystal grow
*PLUS
Components of the solutions
*PLUS
IDConc.Common nameCrystal-IDSol-IDDetails
12.5 mg/mlprotein1drop
2126 mMphosphate1reservoirpH6.2
363 mMsodium citrate1reservoir
428-31 %ammonium sulfate1reservoir

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Data collection

DiffractionMean temperature: 200 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS IV / Detector: IMAGE PLATE / Date: Aug 7, 2001 / Details: Yale Mirrors
RadiationMonochromator: Yale Mirrors / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.2→50 Å / Num. all: 13097 / Num. obs: 13097 / % possible obs: 71.2 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Rmerge(I) obs: 0.064 / Net I/σ(I): 7.6
Reflection shellResolution: 2.2→2.28 Å / Rmerge(I) obs: 0.27
Reflection
*PLUS
Lowest resolution: 50 Å / Num. measured all: 19193
Reflection shell
*PLUS
% possible obs: 66 % / Num. unique obs: 1184

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Processing

Software
NameClassification
SCALEPACKdata scaling
CNSrefinement
CNSphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1F7A

1f7a


Resolution: 2.2→50 Å / Isotropic thermal model: restrained / Cross valid method: THROUGHOUT / σ(F): 0 / σ(I): 0 / Stereochemistry target values: Engh & Huber
Details: NCS RESTRAINTS IMPOSED BETWEEN THE DIMERS (BUT NOT WITHIN THE DIMERS) TO IMPROVE OBSERVABLES TO PARAMETER RATIO.
RfactorNum. reflection% reflectionSelection details
Rfree0.284 1085 -random
Rwork0.223 ---
obs0.223 13097 71.2 %-
all-13097 --
Refinement stepCycle: LAST / Resolution: 2.2→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2844 0 100 28 2972
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_bond_d0.008
X-RAY DIFFRACTIONc_angle_deg1.4
X-RAY DIFFRACTIONc_dihedral_angle_d28.8
X-RAY DIFFRACTIONc_improper_angle_d1.15
LS refinement shellResolution: 2.2→2.28 Å
RfactorNum. reflection% reflection
Rfree0.37 --
Rwork0.32 --
obs-1183 66 %
Refinement
*PLUS
Lowest resolution: 50 Å
Solvent computation
*PLUS
Displacement parameters
*PLUS
Refine LS restraints
*PLUS
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_dihedral_angle_d
X-RAY DIFFRACTIONc_dihedral_angle_deg28.8
X-RAY DIFFRACTIONc_improper_angle_d
X-RAY DIFFRACTIONc_improper_angle_deg1.15

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