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- PDB-1fgc: STRUCTURAL IMPLICATIONS OF DRUG RESISTANT MUTANTS OF HIV-1 PROTEA... -

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Basic information

Entry
Database: PDB / ID: 1fgc
TitleSTRUCTURAL IMPLICATIONS OF DRUG RESISTANT MUTANTS OF HIV-1 PROTEASE: HIGH RESOLUTION CRYSTAL STRUCTURES OF THE MUTANT PROTEASE/SUBSTRATE ANALOG COMPLEXES
ComponentsPROTEASE RETROPEPSIN
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 / host multivesicular body / DNA integration / 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 / host multivesicular body / DNA integration / viral genome integration into host DNA / RNA-directed DNA polymerase / establishment of integrated proviral latency / viral penetration into host nucleus / RNA stem-loop binding / 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 / Reverse transcriptase domain / Reverse transcriptase (RNA-dependent DNA polymerase) / Reverse transcriptase (RT) catalytic domain profile. / Retrovirus capsid, C-terminal / 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-{(2S)-2-[(N-acetyl-L-threonyl-L-isoleucyl)amino]hexyl}-L-norleucyl-L-glutaminyl-N~5~-[amino(iminio)methyl]-L-ornithinamide / Chem-2NC / Gag-Pol polyprotein
Similarity search - Component
Biological speciesHuman immunodeficiency virus 1
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 1.9 Å
AuthorsMahalingam, B. / Louis, J.M. / Harrison, R.W. / Weber, I.T.
CitationJournal: Proteins / Year: 2001
Title: Structural implications of drug-resistant mutants of HIV-1 protease: high-resolution crystal structures of the mutant protease/substrate analogue complexes.
Authors: Mahalingam, B. / Louis, J.M. / Hung, J. / Harrison, R.W. / Weber, I.T.
History
DepositionJul 28, 2000Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 1, 2001Provider: 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 14, 2011Group: Structure summary
Revision 1.4May 9, 2012Group: Non-polymer description
Revision 1.5Feb 27, 2013Group: Other
Revision 1.6Nov 3, 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 1.7Feb 7, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond
Revision 1.8Mar 13, 2024Group: Source and taxonomy / Structure summary / Category: entity / pdbx_entity_src_syn / Item: _entity.details

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
C: PROTEASE RETROPEPSIN
D: PROTEASE RETROPEPSIN
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,2523
Polymers21,4812
Non-polymers7711
Water1,856103
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5340 Å2
ΔGint-29 kcal/mol
Surface area9100 Å2
MethodPISA
Unit cell
Length a, b, c (Å)50.719, 57.452, 61.057
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Cell settingorthorhombic
Space group name H-MP212121
DetailsThe biological assembly is a dimer consisting of chains C and D

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Components

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


Mass: 10740.677 Da / Num. of mol.: 2 / Mutation: Q7K, L33I, L63I, C67A, C95A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human immunodeficiency virus 1 / Genus: Lentivirus / Production host: Escherichia coli (E. coli) / References: UniProt: P04587, HIV-1 retropepsin
#2: Chemical ChemComp-2NC / N-{(2S)-2-[(N-acetyl-L-threonyl-L-isoleucyl)amino]hexyl}-L-norleucyl-L-glutaminyl-N~5~-[amino(iminio)methyl]-L-ornithinamide / p2/NC


Type: peptide-like, Peptide-like / Class: Inhibitor / Mass: 770.983 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C35H68N11O8
Details: SEQUENCE ANALOGOUS TO THE p2-NC PROCESSING SITE IN HIV-1
References: N-{(2S)-2-[(N-acetyl-L-threonyl-L-isoleucyl)amino]hexyl}-L-norleucyl-L-glutaminyl-N~5~-[amino(iminio)methyl]-L-ornithinamide
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 103 / Source method: isolated from a natural source / Formula: H2O
Nonpolymer detailsTHE INHIBITOR 2NC HAS A REDUCED PEPTIDE BOND ISOSTERE [CH2-NH] IN PLACE OF THE SCISSILE AMIDE. THE ...THE INHIBITOR 2NC HAS A REDUCED PEPTIDE BOND ISOSTERE [CH2-NH] IN PLACE OF THE SCISSILE AMIDE. THE COORDINATES OF 2NC WERE DEPOSITED WITH AN EXTRA ATOM O6 AT ZERO OCCUPANCY. THIS ZERO OCCUPANCY O6 HAS BEEN REMOVED FROM THE RELEASED FILE.
Sequence detailsMUTATIONS Q7K, L33I, L63I, C67A, C95A, HAVE BEEN MADE TO STABILIZE THE PROTEASE FROM ...MUTATIONS Q7K, L33I, L63I, C67A, C95A, HAVE BEEN MADE TO 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 Å3/Da / Density % sol: 38.44 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop
Details: CITRATE/PHOSPHATE BUFFER 0.05M, DTT 10MM, DMSO 10%, SATURATED AMMONIUM SULPHAT25-50%, PROTEIN 2-5 MG/ML, pH 5.0-6.5. VAPOR DIFFUSION, HANGING DROP at 298K
Crystal grow
*PLUS
PH range low: 6.5 / PH range high: 5
Components of the solutions
*PLUS
IDConc.Common nameCrystal-IDSol-ID
10.25 Mcitrate1reservoir
20.5 Mphosphate1reservoir
310 %DMSO1reservoir
420-50 %satammonium sulfate1reservoir
52-5 mg/mlprotein1drop

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Data collection

DiffractionMean temperature: 90 K
Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X12B / Wavelength: 0.9464
DetectorType: ADSC QUANTUM 4 / Detector: CCD / Date: Feb 26, 2000
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9464 Å / Relative weight: 1
ReflectionResolution: 1.85→65 Å / Rmerge(I) obs: 0.074
Reflection shellResolution: 1.85→1.93 Å / Rmerge(I) obs: 0.247 / % possible all: 46.8
Reflection
*PLUS
Rmerge(I) obs: 0.075

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Processing

Software
NameVersionClassification
AMoREphasing
X-PLOR3.843refinement
ADSCdata collection
DENZOdata reduction
SCALEPACKdata scaling
RefinementResolution: 1.9→8 Å / Cross valid method: THROUGHOUT / σ(F): 1 / Stereochemistry target values: ENGH & HUBER
RfactorNum. reflection% reflectionSelection details
Rfree0.268 862 6 %Random
Rwork0.212 ---
all-14374 --
Refinement stepCycle: LAST / Resolution: 1.9→8 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1512 0 54 103 1669
Software
*PLUS
Name: X-PLOR / Version: 3.843 / Classification: refinement
Refinement
*PLUS
Highest resolution: 1.9 Å / Lowest resolution: 8 Å / σ(F): 1 / % reflection Rfree: 6 % / Rfactor obs: 0.212
Solvent computation
*PLUS
Displacement parameters
*PLUS
Refine LS restraints
*PLUS
Refine-IDType
X-RAY DIFFRACTIONx_bond_d
X-RAY DIFFRACTIONx_angle_d
X-RAY DIFFRACTIONx_angle_deg
X-RAY DIFFRACTIONx_dihedral_angle_d
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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