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- PDB-1mtb: Viability of a drug-resistant HIV-1 protease mutant: structural i... -

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Basic information

Entry
Database: PDB / ID: 1mtb
TitleViability of a drug-resistant HIV-1 protease mutant: structural insights for better antiviral therapy
ComponentsPROTEASE RETROPEPSIN
KeywordsHYDROLASE/HYDROLASE INHIBITOR / HIV-1 protease / drug resistance / substrate recognition / inhibitor binding / 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
Saquinavir / Chem-ROC / Gag-Pol polyprotein
Similarity search - Component
Biological speciesHuman immunodeficiency virus 1
MethodX-RAY DIFFRACTION / FOURIER SYNTHESIS / Resolution: 2.5 Å
AuthorsPrabu-Jeyabalan, M. / Nalivaika, E.A. / King, N.M. / Schiffer, C.A.
Citation
Journal: J.Virol. / Year: 2003
Title: Viability of 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.A. / 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.A. / 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.
History
DepositionSep 20, 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: Non-polymer description / Version format compliance
Revision 1.3Oct 11, 2017Group: Refinement description / Category: software
Revision 1.4Oct 27, 2021Group: Database references / Derived calculations
Category: database_2 / struct_conn ...database_2 / struct_conn / 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_conn.pdbx_leaving_atom_flag / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.5Feb 14, 2024Group: Data collection / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model / struct_conn
Item: _struct_conn.pdbx_leaving_atom_flag
Revision 1.6Mar 13, 2024Group: Source and taxonomy / Structure summary / Category: entity / pdbx_entity_src_syn / Item: _entity.details
Revision 2.0May 29, 2024Group: Atomic model / Data collection ...Atomic model / Data collection / Derived calculations / Non-polymer description / Structure summary
Category: atom_site / chem_comp ...atom_site / chem_comp / chem_comp_atom / chem_comp_bond / entity / pdbx_entity_nonpoly / pdbx_molecule_features / pdbx_nonpoly_scheme / pdbx_struct_assembly_gen / struct_asym / struct_conn / struct_site / struct_site_gen
Item: _atom_site.auth_asym_id / _atom_site.auth_atom_id ..._atom_site.auth_asym_id / _atom_site.auth_atom_id / _atom_site.auth_comp_id / _atom_site.auth_seq_id / _atom_site.label_asym_id / _atom_site.label_atom_id / _atom_site.label_comp_id / _atom_site.label_entity_id / _chem_comp.formula / _chem_comp.formula_weight / _chem_comp.id / _chem_comp.mon_nstd_flag / _chem_comp.name / _chem_comp.pdbx_synonyms / _chem_comp.type / _pdbx_struct_assembly_gen.asym_id_list / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id / _struct_site.pdbx_num_residues

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: PROTEASE RETROPEPSIN
B: PROTEASE RETROPEPSIN
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,2703
Polymers21,5992
Non-polymers6711
Water72140
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5460 Å2
ΔGint-13 kcal/mol
Surface area8860 Å2
MethodPISA
Unit cell
Length a, b, c (Å)51.439, 60.039, 62.021
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Cell settingorthorhombic
Space group name H-MP212121
DetailsThe entire dimer is provided in the coordinate set and the monomers are distinguished by the chain IDs `A' and `B' + RO 31-8959 (HIV-1 PROTEASE INHIBITOR SAQUINAVIR)

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Components

#1: Protein PROTEASE RETROPEPSIN / E.C.3.4.23.16 / HIV-1 PROTEASE


Mass: 10799.727 Da / Num. of mol.: 2 / Mutation: Q7K, D25N, L63P, V82A
Source method: isolated from a genetically manipulated source
Details: complexed with SAQUINAVIR, RO 31-8959; FDA APPROVED HIV-1 PROTEASE INHIBITOR
Source: (gene. exp.) Human immunodeficiency virus 1 / Genus: Lentivirus / Plasmid: pXC35-pEN18 / Production host: Escherichia coli (E. coli) / Strain (production host): TAP106 / References: UniProt: P03369, HIV-1 retropepsin
#2: Chemical ChemComp-ROC / (2S)-N-[(2S,3R)-4-[(2S,3S,4aS,8aS)-3-(tert-butylcarbamoyl)-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl]-3-hydroxy-1 -phenyl-butan-2-yl]-2-(quinolin-2-ylcarbonylamino)butanediamide / Fortovase / SAQUINAVIR / RO 31-8959


Type: peptide-like, Peptide-like / Class: Inhibitor / Mass: 670.841 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C38H50N6O5 / References: Saquinavir
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 40 / 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: 2.22 Å3/Da / Density % sol: 44.48 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 6.2
Details: sodium phosphate, sodium citrate, ammonium sulphate, pH 6.2, VAPOR DIFFUSION, HANGING DROP at 298K
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: 298 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS IV / Detector: IMAGE PLATE / Date: Aug 8, 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: 2.5→26.6 Å / Num. all: 6743 / Num. obs: 6743 / % possible obs: 93.4 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Biso Wilson estimate: 33.3 Å2 / Rmerge(I) obs: 0.09 / Net I/σ(I): 7
Reflection shellResolution: 2.5→2.59 Å / Rmerge(I) obs: 0.33 / Num. unique all: 496 / % possible all: 71
Reflection
*PLUS
Highest resolution: 2.5 Å / Num. measured all: 28072 / Rmerge(I) obs: 0.08
Reflection shell
*PLUS
Highest resolution: 2.5 Å / % possible obs: 71 % / Num. unique obs: 496 / Rmerge(I) obs: 0.36

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Processing

Software
NameClassification
SCALEPACKdata scaling
CNSrefinement
CNSphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 1F7A

1f7a


Resolution: 2.5→26.56 Å / Rfactor Rfree error: 0.01 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0 / σ(I): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.257 670 10.8 %RANDOM
Rwork0.191 ---
obs0.191 6743 93.4 %-
all-6743 --
Solvent computationSolvent model: FLAT MODEL / Bsol: 57.0169 Å2 / ksol: 0.339017 e/Å3
Displacement parametersBiso mean: 42.9 Å2
Baniso -1Baniso -2Baniso -3
1--9.16 Å20 Å20 Å2
2--1.87 Å20 Å2
3---7.29 Å2
Refine analyzeLuzzati coordinate error free: 0.41 Å / Luzzati sigma a free: 0.53 Å
Refinement stepCycle: LAST / Resolution: 2.5→26.56 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1450 0 49 40 1539
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_bond_d0.008
X-RAY DIFFRACTIONc_angle_deg1.3
X-RAY DIFFRACTIONc_dihedral_angle_d26.5
X-RAY DIFFRACTIONc_improper_angle_d0.95
LS refinement shellResolution: 2.5→2.59 Å / Rfactor Rfree error: 0.062 / Total num. of bins used: 10
RfactorNum. reflection% reflection
Rfree0.36 52 11.2 %
Rwork0.3 411 -
obs-496 71 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1PROTEIN_REP.PARAMPROTEIN.TOP
X-RAY DIFFRACTION2WATER_REP.PARAMWATER.TOP
X-RAY DIFFRACTION3SAQ.PARAMSAQ.TOP
Refinement
*PLUS
Solvent computation
*PLUS
Displacement parameters
*PLUS
Refine LS restraints
*PLUS
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_dihedral_angle_d
X-RAY DIFFRACTIONc_dihedral_angle_deg26.5
X-RAY DIFFRACTIONc_improper_angle_d
X-RAY DIFFRACTIONc_improper_angle_deg0.95
LS refinement shell
*PLUS
Highest resolution: 2.5 Å / Rfactor Rwork: 0.3

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