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- PDB-2wkz: HIV-1 Protease Inhibitors Containing a Tertiary Alcohol in the Tr... -

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Basic information

Entry
Database: PDB / ID: 2wkz
TitleHIV-1 Protease Inhibitors Containing a Tertiary Alcohol in the Transition-State Mimic with Improved Cell-Based Antiviral Activity
ComponentsPROTEASE
KeywordsHYDROLASE / TRANSITION-STATE MIMIC / INHIBITOR
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-5AH / Gag-Pol polyprotein / Gag-Pol polyprotein
Similarity search - Component
Biological speciesHUMAN IMMUNODEFICIENCY VIRUS TYPE 1
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.7 Å
AuthorsMahalingam, A.K. / Axelsson, L. / Ekegren, J.K. / Wannberg, J. / Kihlstrom, J. / Wallberg, H. / Samuelsson, B. / Larhed, M. / Hallberg, A. / Unge, T.
CitationJournal: J.Med.Chem. / Year: 2010
Title: HIV-1 Protease Inhibitors with a Transition-State Mimic Comprising a Tertiary Alcohol: Improved Antiviral Activity in Cells.
Authors: Mahalingam, A.K. / Axelsson, L. / Ekegren, J.K. / Wannberg, J. / Kihlstr, J. / Unge, T. / Wallberg, H. / Samuelsson, B. / Larhed, M. / Hallberg, A.
History
DepositionJun 19, 2009Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 15, 2009Provider: repository / Type: Initial release
Revision 1.1Mar 12, 2014Group: Database references / Source and taxonomy ...Database references / Source and taxonomy / Structure summary / Version format compliance
Revision 1.2Jan 17, 2018Group: Data collection / Category: diffrn_source / Item: _diffrn_source.pdbx_synchrotron_site
Revision 1.3Dec 13, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_initial_refinement_model / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Remark 700 SHEET DETERMINATION METHOD: DSSP THE SHEETS PRESENTED AS "AB" IN EACH CHAIN ON SHEET RECORDS BELOW ... SHEET DETERMINATION METHOD: DSSP THE SHEETS PRESENTED AS "AB" IN EACH CHAIN ON SHEET RECORDS BELOW IS ACTUALLY AN 7-STRANDED BARREL THIS IS REPRESENTED BY A 8-STRANDED SHEET IN WHICH THE FIRST AND LAST STRANDS ARE IDENTICAL.

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: PROTEASE
B: PROTEASE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,3013
Polymers21,6082
Non-polymers6941
Water3,063170
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4060 Å2
ΔGint-22.4 kcal/mol
Surface area9520 Å2
MethodPISA
Unit cell
Length a, b, c (Å)58.420, 86.080, 46.510
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP21212

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Components

#1: Protein PROTEASE / RETROPEPSIN / PR / HIV-1 PROTEASE


Mass: 10803.756 Da / Num. of mol.: 2 / Fragment: RESIDUES 501-599
Source method: isolated from a genetically manipulated source
Details: COMPLEX WITH INHIBITOR COMPOUND AHA599
Source: (gene. exp.) HUMAN IMMUNODEFICIENCY VIRUS TYPE 1 (Z2/CDC-Z34 ISOLATE)
Variant: GROUP M SUBTYPE D / Plasmid: PEXP5 / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21 / Variant (production host): AI
References: UniProt: P03366, UniProt: P12499*PLUS, HIV-1 retropepsin
#2: Chemical ChemComp-5AH / METHYL [(1S)-1-({2-[(3S)-3-BENZYL-3-HYDROXY-4-{[(1S,2R)-2-HYDROXY-2,3-DIHYDRO-1H-INDEN-1-YL]AMINO}-4-OXOBUTYL]-2-(4-PYRIDIN-2-YLBENZYL)HYDRAZINO}CARBONYL)-2,2-DIMETHYLPROPYL]CARBAMATE


Mass: 693.831 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C40H47N5O6
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 170 / 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: 2.7 Å3/Da / Density % sol: 53 % / Description: NONE
Crystal growpH: 5
Details: PROTEASE 2 MG/ML PRECIPITANT 0.7 M NACL, 100 MM MES PH 5.5

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Data collection

DiffractionMean temperature: 180 K
Diffraction sourceSource: SYNCHROTRON / Site: MAX II / Beamline: I911-5 / Wavelength: 1.06
DetectorType: MARRESEARCH / Detector: CCD / Date: Jul 12, 2005
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.06 Å / Relative weight: 1
ReflectionNum. obs: 26363 / % possible obs: 99.7 % / Observed criterion σ(I): 2 / Redundancy: 3.9 % / Biso Wilson estimate: 12.7 Å2 / Rmerge(I) obs: 0.1 / Net I/σ(I): 5.2
Reflection shellResolution: 1.7→1.79 Å / Redundancy: 3.8 % / Rmerge(I) obs: 0.2 / Mean I/σ(I) obs: 4.2 / % possible all: 99

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Processing

Software
NameVersionClassification
CNS1.1refinement
MOSFLMdata reduction
CCP4data scaling
CNSphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1D4J

1d4j


Resolution: 1.7→45 Å / Data cutoff high absF: 10000 / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.2516 1312 5 %RANDOM
Rwork0.2288 ---
obs0.2288 26363 99.5 %-
Solvent computationBsol: 41.7359 Å2 / ksol: 0.373272 e/Å3
Displacement parametersBiso mean: 13.6 Å2
Baniso -1Baniso -2Baniso -3
1-0.468 Å20 Å20 Å2
2---1.05 Å20 Å2
3---0.581 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.25 Å0.22 Å
Luzzati d res low-5 Å
Luzzati sigma a0.1 Å0.04 Å
Refinement stepCycle: LAST / Resolution: 1.7→45 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1516 0 51 170 1737
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_bond_d0.006509
X-RAY DIFFRACTIONc_bond_d_na
X-RAY DIFFRACTIONc_bond_d_prot
X-RAY DIFFRACTIONc_angle_d
X-RAY DIFFRACTIONc_angle_d_na
X-RAY DIFFRACTIONc_angle_d_prot
X-RAY DIFFRACTIONc_angle_deg1.26172
X-RAY DIFFRACTIONc_angle_deg_na
X-RAY DIFFRACTIONc_angle_deg_prot
X-RAY DIFFRACTIONc_dihedral_angle_d25.1
X-RAY DIFFRACTIONc_dihedral_angle_d_na
X-RAY DIFFRACTIONc_dihedral_angle_d_prot
X-RAY DIFFRACTIONc_improper_angle_d0.89
X-RAY DIFFRACTIONc_improper_angle_d_na
X-RAY DIFFRACTIONc_improper_angle_d_prot
X-RAY DIFFRACTIONc_mcbond_it
X-RAY DIFFRACTIONc_mcangle_it
X-RAY DIFFRACTIONc_scbond_it
X-RAY DIFFRACTIONc_scangle_it
LS refinement shellResolution: 1.7→1.81 Å / Rfactor Rfree error: 0.018 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.259 209 4.8 %
Rwork0.242 4118 -
obs--99.8 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1559.PAR559.TOP
X-RAY DIFFRACTION2PROTEIN_REP.PARAMPROTEIN.TOP

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