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- PDB-4a6b: Stereoselective Synthesis, X-ray Analysis, and Biological Evaluat... -

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Basic information

Entry
Database: PDB / ID: 4a6b
TitleStereoselective Synthesis, X-ray Analysis, and Biological Evaluation of a New Class of Lactam Based HIV-1 Protease Inhibitors
ComponentsPOL PROTEIN
KeywordsHYDROLASE / GAMMA-BUTYROL-LACTAM
Function / homology
Function and homology information


HIV-1 retropepsin / : / retroviral ribonuclease H / exoribonuclease H / : / exoribonuclease H activity / host multivesicular body / DNA integration / RNA-directed DNA polymerase / viral genome integration into host DNA ...HIV-1 retropepsin / : / retroviral ribonuclease H / exoribonuclease H / : / exoribonuclease H activity / host multivesicular body / DNA integration / RNA-directed DNA polymerase / viral genome integration into host DNA / viral penetration into host nucleus / establishment of integrated proviral latency / RNA-directed DNA polymerase activity / Transferases; Transferring phosphorus-containing groups; Nucleotidyltransferases / RNA-DNA hybrid ribonuclease activity / viral nucleocapsid / DNA recombination / Hydrolases; Acting on ester bonds / DNA-directed DNA polymerase / aspartic-type endopeptidase activity / DNA-directed DNA polymerase activity / symbiont entry into host cell / symbiont-mediated suppression of host gene expression / lipid binding / host cell nucleus / structural molecule activity / host cell plasma membrane / virion membrane / proteolysis / DNA binding / RNA 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. / Retroviral nucleocapsid Gag protein p24, C-terminal domain / Gag protein p24 C-terminal domain / Retropepsin-like catalytic domain / Matrix protein, lentiviral and alpha-retroviral, N-terminal / Ribonuclease H domain / RNase H type-1 domain profile. / Reverse transcriptase (RNA-dependent DNA polymerase) / Reverse transcriptase domain / Reverse transcriptase (RT) catalytic domain profile. / Retropepsins / Retroviral aspartyl protease / Aspartyl protease, retroviral-type family profile. / Peptidase A2A, retrovirus, catalytic / Retrovirus capsid, C-terminal / Retroviral matrix protein / Retrovirus capsid, N-terminal / zinc finger / Zinc knuckle / Zinc finger, CCHC-type superfamily / Cathepsin D, subunit A; domain 1 / Acid Proteases / Zinc finger, CCHC-type / Zinc finger CCHC-type profile. / Ribonuclease H superfamily / Aspartic peptidase, active site / Eukaryotic and viral aspartyl proteases active site. / Aspartic peptidase domain superfamily / Ribonuclease H-like superfamily / Reverse transcriptase/Diguanylate cyclase domain / DNA/RNA polymerase superfamily / Beta Barrel / Mainly Beta
Similarity search - Domain/homology
Chem-QG8 / Gag-Pol polyprotein / 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. / Unge, J. / Arvela, R.K. / Wallberg, H. / Vrang, L. / Rosenquist, A. ...Wu, X. / Ohrngren, P. / Joshi, A.A. / Trejos, A. / Persson, M. / Unge, J. / Arvela, R.K. / Wallberg, H. / Vrang, L. / Rosenquist, A. / Samuelsson, B.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
DepositionNov 1, 2011Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 9, 2012Provider: repository / Type: Initial release
Revision 1.1Jan 17, 2018Group: Data collection / Category: diffrn_source / Item: _diffrn_source.pdbx_synchrotron_site
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: POL PROTEIN
B: POL PROTEIN
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,2843
Polymers21,5512
Non-polymers7331
Water2,576143
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4140 Å2
ΔGint-24.4 kcal/mol
Surface area9410 Å2
MethodPISA
Unit cell
Length a, b, c (Å)58.400, 86.500, 46.300
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 POL 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, UniProt: P35963*PLUS, HIV-1 retropepsin
#2: Chemical ChemComp-QG8 / METHYL ((S)-1-(2-([1,1'-BIPHENYL]-4-YLMETHYL)-2-(3-((3S,4S)-3-BENZYL-4-HYDROXY-1-((1S,2R)-2-HYDROXY-2,3-DIHYDRO-1H-INDEN-1-YL)-2-OXOPYRROLIDIN-3-YL)PROPYL)HYDRAZINYL)-3,3-DIMETHYL-1-OXOBUTAN-2-YL)CARBAMATE


Mass: 732.907 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C44H52N4O6
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 143 / 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: 54.67 % / Description: NONE

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: MAX II / Beamline: I911-3 / Wavelength: 1
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Jun 28, 2010 / Details: MIRROR
RadiationMonochromator: SI(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.8→48.42 Å / Num. obs: 20303 / % possible obs: 95.8 % / Observed criterion σ(I): 2 / Redundancy: 4.6 % / Biso Wilson estimate: 11.6 Å2 / Rmerge(I) obs: 0.07 / Net I/σ(I): 8.9
Reflection shellResolution: 1.8→1.9 Å / Redundancy: 4.5 % / Rmerge(I) obs: 0.22 / Mean I/σ(I) obs: 3.8 / % possible all: 95.8

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Processing

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

Resolution: 1.8→20.89 Å / Rfactor Rfree error: 0.008 / Data cutoff high absF: 1184899.76 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.253 1051 5 %RANDOM
Rwork0.223 ---
obs0.223 21203 94.6 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 44.219 Å2 / ksol: 0.362279 e/Å3
Displacement parametersBiso mean: 17.3 Å2
Baniso -1Baniso -2Baniso -3
1-1.78 Å20 Å20 Å2
2---0.7 Å20 Å2
3----1.09 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.26 Å0.22 Å
Luzzati d res low-5 Å
Luzzati sigma a0.09 Å0.05 Å
Refinement stepCycle: LAST / Resolution: 1.8→20.89 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1512 0 54 143 1709
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_bond_d0.007
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_deg1.2
X-RAY DIFFRACTIONc_angle_deg_na
X-RAY DIFFRACTIONc_angle_deg_prot
X-RAY DIFFRACTIONc_dihedral_angle_d25.3
X-RAY DIFFRACTIONc_dihedral_angle_d_na
X-RAY DIFFRACTIONc_dihedral_angle_d_prot
X-RAY DIFFRACTIONc_improper_angle_d0.85
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: 0.019 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.251 170 4.7 %
Rwork0.238 3413 -
obs--97.4 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1PROTEIN_REP.PARAMPROTEIN.TOP
X-RAY DIFFRACTION2INH_PAR.TXTINH_TOP.TXT
X-RAY DIFFRACTION3WATER_REP.PARAMWATER.TOP

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