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- PDB-1c6z: ALTERNATE BINDING SITE FOR THE P1-P3 GROUP OF A CLASS OF POTENT H... -

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Basic information

Entry
Database: PDB / ID: 1c6z
TitleALTERNATE BINDING SITE FOR THE P1-P3 GROUP OF A CLASS OF POTENT HIV-1 PROTEASE INHIBITORS AS A RESULT OF CONCERTED STRUCTURAL CHANGE IN 80'S LOOP.
ComponentsPROTEIN (PROTEASE)
KeywordsHYDROLASE/HYDROLASE INHIBITOR / hydrolase-hydrolase inhibitor complex
Function / homology
Function and homology information


aspartic-type endopeptidase activity / proteolysis
Similarity search - Function
Retropepsin-like catalytic domain / Retropepsins / Retroviral aspartyl protease / Aspartyl protease, retroviral-type family profile. / Peptidase A2A, retrovirus, catalytic / Cathepsin D, subunit A; domain 1 / Acid Proteases / Aspartic peptidase, active site / Eukaryotic and viral aspartyl proteases active site. / Aspartic peptidase domain superfamily ...Retropepsin-like catalytic domain / Retropepsins / Retroviral aspartyl protease / Aspartyl protease, retroviral-type family profile. / Peptidase A2A, retrovirus, catalytic / Cathepsin D, subunit A; domain 1 / Acid Proteases / Aspartic peptidase, active site / Eukaryotic and viral aspartyl proteases active site. / Aspartic peptidase domain superfamily / Beta Barrel / Mainly Beta
Similarity search - Domain/homology
Saquinavir / Chem-ROC / Protease
Similarity search - Component
Biological speciesHuman immunodeficiency virus 1
MethodX-RAY DIFFRACTION / Resolution: 2.5 Å
AuthorsMunshi, S.
Citation
Journal: Acta Crystallogr.,Sect.D / Year: 2000
Title: An alternate binding site for the P1-P3 group of a class of potent HIV-1 protease inhibitors as a result of concerted structural change in the 80s loop of the protease.
Authors: Munshi, S. / Chen, Z. / Yan, Y. / Li, Y. / Olsen, D.B. / Schock, H.B. / Galvin, B.B. / Dorsey, B. / Kuo, L.C.
#1: Journal: J.Med.Chem. / Year: 1991
Title: Novel Binding Mode of Highly Potent HIV-Proteinase Inhibitors Incorporating the (R)-Hydroxyethylamine Isostere
Authors: Krohn, A. / Redshaw, S. / Ritchie, J.C. / Graves, B.J. / Hatada, M.H.
History
DepositionDec 28, 1999Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 28, 2000Provider: repository / Type: Initial release
Revision 1.1Apr 26, 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 1.4Dec 27, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / entity / pdbx_entity_nonpoly / struct_site
Item: _chem_comp.name / _chem_comp.pdbx_synonyms ..._chem_comp.name / _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _entity.pdbx_description / _pdbx_entity_nonpoly.name / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: PROTEIN (PROTEASE)
B: PROTEIN (PROTEASE)
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,2743
Polymers21,6032
Non-polymers6711
Water1,36976
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5170 Å2
ΔGint-29 kcal/mol
Surface area9200 Å2
MethodPISA
Unit cell
Length a, b, c (Å)88.13, 88.14, 32.99
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 PROTEIN (PROTEASE)


Mass: 10801.674 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Details: NY5 ISOLATE / Source: (gene. exp.) Human immunodeficiency virus 1 / Genus: Lentivirus / Gene: NY5 ISOLATE / Production host: Escherichia coli (E. coli)
References: UniProt: O09893, Hydrolases; Acting on peptide bonds (peptidases); Metalloendopeptidases
#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 / Saquinavir


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


Mass: 18.015 Da / Num. of mol.: 76 / Source method: isolated from a natural source / Formula: H2O
Compound details9X MUTANT PROTEASE HAS NINE POINT MUTATIONS COMPARED TO WILD TYPE: ...9X MUTANT PROTEASE HAS NINE POINT MUTATIONS COMPARED TO WILD TYPE: L10V,K20M,L24I,S37D,M46I,I54V,L63P,A71V,V82T THERE IS ONE PROTEASE DIMER IN AN ASYMMETRICAL UNIT. THE TWO MOLECULES ARE LABELED AS CHAIN A AND CHAIN B. THERE is one SAQUINAVIR INHIBITOR MOLECULE LABELED AS ROC 505 WITH alternate conformations of OCCUPANCY 0.5
Nonpolymer detailsTHE INHIBITOR ROC IS A HYDROXYETHYLAMINE CONTAINING TRANSITION STATE MIMETIC.

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.96 Å3/Da / Density % sol: 58.5 %
Crystal growDetails: CRYSTALS OBTAINED BY CO-CRYSTALLIZATION AT PH 5.2, USING 0.6M NaCl AS PRECIPITATING AGENT IN 0.1M SODIUM ACETATE BUFFER. PROTEIN WAS AT 5.5 MG/ML CONCENTRATION.
Crystal grow
*PLUS
pH: 5 / Method: vapor diffusion, hanging drop
Details: inhibitor-protein mixture and the reservoir solution were mixed in a 1:1(v/v) ratio
Components of the solutions
*PLUS
IDConc.Common nameCrystal-IDSol-IDChemical formulaDetails
14-6 mg/mlenzyme1drop
210 mMMES1drop
31 mMdithiothreitol1drop
41 mMEDTA1drop
53 mM1dropNaN3
70.6-0.8 M1reservoirNaCl
80.1 M1reservoirNaOAc
6inhibitor1dropmixed with the protein containing buffer in a molar ratio of 1:3 to 1:5, with a final DMSO concentration of 2-5%

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Data collection

RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthRelative weight: 1
ReflectionNum. all: 41654 / Num. obs: 7717 / % possible obs: 82 % / Rmerge(I) obs: 0.062
Reflection shellResolution: 2.5→2.59 Å / % possible all: 73
Reflection
*PLUS
Highest resolution: 2.5 Å / Lowest resolution: 20 Å / Num. measured all: 41654
Reflection shell
*PLUS
% possible obs: 73 % / Num. unique obs: 677 / Num. measured obs: 2345 / Rmerge(I) obs: 0.224 / Mean I/σ(I) obs: 4

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Processing

SoftwareName: X-PLOR / Classification: refinement
RefinementResolution: 2.5→8 Å / Rfactor Rfree: 0.29 / Rfactor Rwork: 0.18 / Rfactor obs: 0.18 / σ(F): 2
Refinement stepCycle: LAST / Resolution: 2.5→8 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1514 0 49 76 1639
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONx_bond_d0.017
X-RAY DIFFRACTIONx_bond_d_na
X-RAY DIFFRACTIONx_bond_d_prot
X-RAY DIFFRACTIONx_angle_d
X-RAY DIFFRACTIONx_angle_d_na
X-RAY DIFFRACTIONx_angle_d_prot
X-RAY DIFFRACTIONx_angle_deg2.5
X-RAY DIFFRACTIONx_angle_deg_na
X-RAY DIFFRACTIONx_angle_deg_prot
X-RAY DIFFRACTIONx_dihedral_angle_d
X-RAY DIFFRACTIONx_dihedral_angle_d_na
X-RAY DIFFRACTIONx_dihedral_angle_d_prot
X-RAY DIFFRACTIONx_improper_angle_d
X-RAY DIFFRACTIONx_improper_angle_d_na
X-RAY DIFFRACTIONx_improper_angle_d_prot
X-RAY DIFFRACTIONx_mcbond_it
X-RAY DIFFRACTIONx_mcangle_it
X-RAY DIFFRACTIONx_scbond_it
X-RAY DIFFRACTIONx_scangle_it

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