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- PDB-4a4q: Stereoselective Synthesis, X-ray Analysis, and Biological Evaluat... -

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Basic information

Entry
Database: PDB / ID: 4a4q
TitleStereoselective Synthesis, X-ray Analysis, and Biological Evaluation of a New Class of Lactam Based HIV-1 Protease Inhibitors
ComponentsPROTEASE
KeywordsHYDROLASE / GAMMA-BUTYROL-LACTAM / INHIBITOR
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
Chem-UX9 / Pol protein
Similarity search - Component
Biological speciesHUMAN IMMUNODEFICIENCY VIRUS
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.8 Å
AuthorsWu, X. / Ohrngren, P. / Joshi, A.A. / Trejos, A. / Persson, M. / Arvela, R.K. / Wallberg, H. / Vrang, L. / Rosenquist, A. / Samuelsson, B. ...Wu, X. / Ohrngren, P. / Joshi, A.A. / Trejos, A. / Persson, M. / Arvela, R.K. / Wallberg, H. / Vrang, L. / Rosenquist, A. / Samuelsson, B. / Unge, J. / Larhed, M.
CitationJournal: J.Med.Chem. / Year: 2012
Title: Synthesis, X-Ray Analysis, and Biological Evaluation of a New Class of Stereopure Lactam-Based HIV-1 Protease Inhibitors.
Authors: Wu, X. / Ohrngren, P. / Joshi, A.A. / Trejos, A. / Persson, M. / Arvela, R.K. / Wallberg, H. / Vrang, L. / Rosenquist, A. / Samuelsson, B.B. / Unge, J. / Larhed, M.
History
DepositionOct 19, 2011Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 7, 2012Provider: repository / Type: Initial release
Revision 1.1Feb 5, 2014Group: Database references / Structure summary
Revision 1.2Jan 17, 2018Group: Data collection / Category: diffrn_source / Item: _diffrn_source.pdbx_synchrotron_site
Revision 1.3May 1, 2024Group: 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_sheet / 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_sheet.number_strands / _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 6-STRANDED BARREL THIS IS REPRESENTED BY A 7-STRANDED SHEET IN WHICH THE FIRST AND LAST STRANDS ARE IDENTICAL. THE SHEETS PRESENTED AS "BA" IN EACH CHAIN ON SHEET RECORDS BELOW IS ACTUALLY AN 6-STRANDED BARREL THIS IS REPRESENTED BY A 7-STRANDED SHEET IN WHICH THE FIRST AND LAST STRANDS ARE IDENTICAL.

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: PROTEASE
B: PROTEASE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,2713
Polymers21,5512
Non-polymers7201
Water3,189177
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4100 Å2
ΔGint-23.6 kcal/mol
Surface area9320 Å2
MethodPISA
Unit cell
Length a, b, c (Å)58.374, 86.005, 46.536
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


Mass: 10775.659 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HUMAN IMMUNODEFICIENCY VIRUS / Strain: 99HHP1 / Production host: ESCHERICHIA COLI (E. coli) / References: UniProt: Q8Q3H0, HIV-1 retropepsin
#2: Chemical ChemComp-UX9 / methyl [(2S)-1-{2-(2-{(3R,4S)-3-benzyl-4-hydroxy-1-[(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]-2-oxopyrrolidin-3-yl}ethyl)-2-[4-(pyridin-4-yl)benzyl]hydrazinyl}-3,3-dimethyl-1-oxobutan-2-yl]carbamate


Mass: 719.868 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C42H49N5O6
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 177 / 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: 2.71 Å3/Da / Density % sol: 54.62 % / Description: NONE

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: MAX II / Beamline: I911-2 / Wavelength: 1.0379
DetectorType: MARRESEARCH SX-165 / Detector: CCD / Date: Dec 12, 2007 / Details: MIRROR
RadiationMonochromator: SI(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0379 Å / Relative weight: 1
ReflectionResolution: 1.8→19.3 Å / Num. obs: 18880 / % possible obs: 86.3 % / Observed criterion σ(I): 2 / Redundancy: 4.3 % / Biso Wilson estimate: 8.3 Å2 / Rmerge(I) obs: 0.07 / Net I/σ(I): 6.3
Reflection shellResolution: 1.8→1.9 Å / Redundancy: 4.1 % / Rmerge(I) obs: 0.14 / Mean I/σ(I) obs: 2.2 / % possible all: 89.7

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Processing

Software
NameVersionClassification
CNS1.3refinement
MOSFLMdata reduction
SCALAdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: HIV-1 PROTEASE

Resolution: 1.8→18.72 Å / Rfactor Rfree error: 0.008 / Data cutoff high absF: 1235760.73 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0 / Details: BULK SOLVENT MODEL USED
RfactorNum. reflection% reflectionSelection details
Rfree0.233 951 5 %RANDOM
Rwork0.201 ---
obs0.201 18873 84.3 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 55.2793 Å2 / ksol: 0.42 e/Å3
Displacement parametersBiso mean: 13.7 Å2
Baniso -1Baniso -2Baniso -3
1-2.88 Å20 Å20 Å2
2---2.19 Å20 Å2
3----0.68 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.25 Å0.2 Å
Luzzati d res low-5 Å
Luzzati sigma a0.18 Å0.07 Å
Refinement stepCycle: LAST / Resolution: 1.8→18.72 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1512 0 53 177 1742
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_bond_d0.006
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_deg1.3
X-RAY DIFFRACTIONc_angle_deg_na
X-RAY DIFFRACTIONc_angle_deg_prot
X-RAY DIFFRACTIONc_dihedral_angle_d24.9
X-RAY DIFFRACTIONc_dihedral_angle_d_na
X-RAY DIFFRACTIONc_dihedral_angle_d_prot
X-RAY DIFFRACTIONc_improper_angle_d0.8
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
Refine LS restraints NCSNCS model details: NONE
LS refinement shellResolution: 1.8→1.91 Å / Rfactor Rfree error: 0.024 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.301 152 4.7 %
Rwork0.221 3095 -
obs--88.5 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1PROTEIN_REP.PARAMPROTEIN.TOP
X-RAY DIFFRACTION2DNA-RNA_REP.PARAMDNA-RNA.TOP
X-RAY DIFFRACTION3WATER_REP.PARAMWATER.TOP
X-RAY DIFFRACTION4ION.PARAMION.TOP
X-RAY DIFFRACTION5CARBOHYDRATE.PARAMCARBOHYDRATE.TOP
X-RAY DIFFRACTION6INH.PARINH.TOP

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