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- PDB-1izi: Inhibitor of HIV protease with unusual binding mode potently inhi... -

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Basic information

Entry
Database: PDB / ID: 1izi
TitleInhibitor of HIV protease with unusual binding mode potently inhibiting multi-resistant protease mutants
Componentsproteinase
KeywordsHYDROLASE / HIV-1 proteinase / triple mutant / potent inhibitor / subsite binding
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 / viral genome integration into host DNA / RNA-directed DNA polymerase / establishment of integrated proviral latency / RNA stem-loop binding ...HIV-1 retropepsin / symbiont-mediated activation of host apoptosis / retroviral ribonuclease H / exoribonuclease H / exoribonuclease H activity / DNA integration / viral genome integration into host DNA / RNA-directed DNA polymerase / establishment of integrated proviral latency / RNA stem-loop binding / viral penetration into host nucleus / host multivesicular body / 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
Chem-Q50 / Gag-Pol polyprotein / Protease
Similarity search - Component
Biological speciesHuman immunodeficiency virus 1
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.15 Å
AuthorsWeber, J. / Mesters, J.R. / Lepsik, M. / Prejdova, J. / Svec, M. / Sponarova, J. / Mlcochova, P. / Skalicka, K. / Strisovsky, K. / Uhlikova, T. ...Weber, J. / Mesters, J.R. / Lepsik, M. / Prejdova, J. / Svec, M. / Sponarova, J. / Mlcochova, P. / Skalicka, K. / Strisovsky, K. / Uhlikova, T. / Soucek, M. / Machala, L. / Stankova, M. / Vondrasek, J. / Klimkait, T. / Kraeusslich, H.-G. / Hilgenfeld, R. / Konvalinka, J.
CitationJournal: J.MOL.BIOL. / Year: 2002
Title: Unusual Binding Mode of an HIV-1 Protease Inhibitor Explains its Potency against Multi-drug-resistant Virus Strains
Authors: Weber, J. / Mesters, J.R. / Lepsik, M. / Prejdova, J. / Svec, M. / Sponarova, J. / Mlcochova, P. / Skalicka, K. / Strisovsky, K. / Uhlikova, T. / Soucek, M. / Machala, L. / Stankova, M. / ...Authors: Weber, J. / Mesters, J.R. / Lepsik, M. / Prejdova, J. / Svec, M. / Sponarova, J. / Mlcochova, P. / Skalicka, K. / Strisovsky, K. / Uhlikova, T. / Soucek, M. / Machala, L. / Stankova, M. / Vondrasek, J. / Klimkait, T. / Kraeusslich, H.-G. / Hilgenfeld, R. / Konvalinka, J.
History
DepositionOct 2, 2002Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Dec 23, 2002Provider: repository / Type: Initial release
Revision 1.1Apr 27, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Nov 10, 2021Group: Data collection / Database references / Derived calculations
Category: database_2 / diffrn_source ...database_2 / diffrn_source / 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 / _diffrn_source.pdbx_synchrotron_site / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.4Oct 25, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model / struct_ncs_dom_lim
Item: _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.end_auth_comp_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: proteinase
B: proteinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,4505
Polymers21,6942
Non-polymers7573
Water73941
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5330 Å2
ΔGint-47 kcal/mol
Surface area8730 Å2
MethodPISA
Unit cell
Length a, b, c (Å)61.788, 61.788, 82.821
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number169
Space group name H-MP61
DetailsThe biological assembly is the homodimer as found in the asymmetric unit

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Components

#1: Protein proteinase / protease


Mass: 10846.781 Da / Num. of mol.: 2 / Mutation: A71V, V82T, I84V
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human immunodeficiency virus 1 / Genus: Lentivirus / Plasmid: pET24a / Species (production host): Escherichia coli / Production host: Escherichia coli BL21 (bacteria) / Strain (production host): BL21
References: UniProt: Q90EB9, UniProt: P03367*PLUS, HIV-1 retropepsin
#2: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#3: Chemical ChemComp-Q50 / {(1S)-1-BENZYL-4-[3-CARBAMOYL-1-(1-CARBAMOYL-2-PHENYL-ETHYLCARBAMOYL)-(S)-PROPYLCARBAMOYL]-2-OXO-5-PHENYL-PENTYL}-CARBAMIC ACID TERT-BUTYL ESTER


Mass: 685.809 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C38H47N5O7
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 41 / 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: 2.1 Å3/Da / Density % sol: 41.5 %
Crystal growTemperature: 294 K / Method: vapor diffusion, hanging drop / pH: 5
Details: MES, EDTA, DTT, NaCl, pH 5, VAPOR DIFFUSION, HANGING DROP, temperature 294K
Crystal grow
*PLUS
Temperature: 4 ℃ / pH: 6
Components of the solutions
*PLUS
IDConc.Common nameCrystal-IDSol-IDDetailsChemical formula
125 mMMES1droppH6.0
210 %(v/v)glycerol1drop
31 mMEDTA1drop
41 mMdithiothreitol1drop
52-5 mg/mlprotein1drop
60.7-1.0 M1reservoirKCl
7100 mMMES1reservoirpH6.0
83 mM1reservoirNaN3
910 mMdithiothreitol1reservoir

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: EMBL/DESY, HAMBURG / Beamline: X13 / Wavelength: 0.802 Å
DetectorType: MARRESEARCH / Detector: CCD / Date: Aug 10, 2001
RadiationMonochromator: SAGITALLY FOCUSED Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.802 Å / Relative weight: 1
ReflectionResolution: 2.15→40 Å / Num. all: 9695 / Num. obs: 9695 / % possible obs: 98.9 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 5.62 % / Biso Wilson estimate: 33.5 Å2 / Rmerge(I) obs: 0.06 / Net I/σ(I): 19.76
Reflection shellResolution: 2.15→2.23 Å / Rmerge(I) obs: 0.323 / Num. unique all: 952 / % possible all: 99.9
Reflection
*PLUS
Highest resolution: 2.1 Å / Rmerge(I) obs: 0.06

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Processing

Software
NameVersionClassification
DENZOdata reduction
SCALEPACKdata scaling
AMoREphasing
REFMAC5.1.24refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1IZH

1izh


Resolution: 2.15→53.45 Å / Cor.coef. Fo:Fc: 0.959 / Cor.coef. Fo:Fc free: 0.923 / SU B: 6.383 / SU ML: 0.162 / Cross valid method: THROUGHOUT / σ(F): 0 / σ(I): 0 / ESU R: 0.303 / ESU R Free: 0.224 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.24797 464 4.8 %RANDOM
Rwork0.18942 ---
all0.19202 9229 --
obs0.19202 9229 99.23 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 38.732 Å2
Baniso -1Baniso -2Baniso -3
1-0.4 Å20.2 Å20 Å2
2--0.4 Å20 Å2
3----0.6 Å2
Refinement stepCycle: LAST / Resolution: 2.15→53.45 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1476 0 52 41 1569
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0230.0221554
X-RAY DIFFRACTIONr_bond_other_d0.0010.021484
X-RAY DIFFRACTIONr_angle_refined_deg2.2792.0112113
X-RAY DIFFRACTIONr_angle_other_deg0.90433438
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.7255196
X-RAY DIFFRACTIONr_chiral_restr0.1260.2252
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.021702
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02282
X-RAY DIFFRACTIONr_nbd_refined0.2090.3277
X-RAY DIFFRACTIONr_nbd_other0.2720.31778
X-RAY DIFFRACTIONr_nbtor_other0.1050.51021
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.190.596
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.0830.38
X-RAY DIFFRACTIONr_symmetry_vdw_other0.2080.328
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.8080.53
X-RAY DIFFRACTIONr_mcbond_it1.8552970
X-RAY DIFFRACTIONr_mcangle_it3.01931567
X-RAY DIFFRACTIONr_scbond_it1.8672584
X-RAY DIFFRACTIONr_scangle_it3.0743546
LS refinement shellResolution: 2.151→2.207 Å / Total num. of bins used: 20 /
RfactorNum. reflection
Rfree0.363 39
Rwork0.228 676
Refinement
*PLUS
Solvent computation
*PLUS
Displacement parameters
*PLUS

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