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- PDB-4cps: Macrocyclic Transition-State Mimicking HIV-1 Protease Inhibitors ... -

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Basic information

Entry
Database: PDB / ID: 4cps
TitleMacrocyclic Transition-State Mimicking HIV-1 Protease Inhibitors Encompassing a Tertiary Alcohol
ComponentsPROTEASE
KeywordsHYDROLASE / INHIBITOR / RATIONAL DRUG DESIGN
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 / symbiont-mediated suppression of host gene expression / 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 / Hydrolases; Acting on ester bonds / aspartic-type endopeptidase activity / DNA-directed DNA polymerase activity / symbiont entry into host cell / viral translational frameshifting / lipid binding / host cell nucleus / host cell plasma membrane / structural molecule activity / virion membrane / 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 / RNase H type-1 domain profile. / Ribonuclease H domain / Matrix protein, lentiviral and alpha-retroviral, N-terminal / Retroviral nucleocapsid Gag protein p24, C-terminal domain / Gag protein p24 C-terminal domain / Reverse transcriptase domain / Reverse transcriptase (RT) catalytic domain profile. / Retropepsins / Retroviral aspartyl protease / Aspartyl protease, retroviral-type family profile. / Peptidase A2A, retrovirus, catalytic / Reverse transcriptase (RNA-dependent DNA polymerase) / Retroviral matrix protein / Retrovirus capsid, C-terminal / 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. / Aspartic peptidase, active site / Eukaryotic and viral aspartyl proteases active site. / Ribonuclease H superfamily / 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-1T8 / Gag-Pol polyprotein
Similarity search - Component
Biological speciesHUMAN IMMUNODEFICIENCY VIRUS
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.55 Å
AuthorsDeRosa, M. / Unge, J. / Motwani, H.V. / Rosenquist, A. / Vrang, L. / Wallberg, H. / Larhed, M.
CitationJournal: J.Med.Chem. / Year: 2014
Title: Synthesis of P1'-Functionalized Macrocyclic Transition-State Mimicking HIV-1 Protease Inhibitors Encompassing a Tertiary Alcohol.
Authors: De Rosa, M. / Unge, J. / Motwani, H.V. / Rosenquist, A. / Vrang, L. / Wallberg, H. / Larhed, M.
History
DepositionFeb 8, 2014Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 17, 2014Provider: repository / Type: Initial release
Revision 1.1Jan 17, 2018Group: Data collection / Category: diffrn_source / Item: _diffrn_source.pdbx_synchrotron_site
Revision 1.2May 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

Downloads & links

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Assembly

Deposited unit
A: PROTEASE
B: PROTEASE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,3856
Polymers21,5512
Non-polymers8334
Water4,900272
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4350 Å2
ΔGint-48.2 kcal/mol
Surface area9490 Å2
MethodPISA
Unit cell
Length a, b, c (Å)58.160, 86.003, 46.497
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 / PR / RETROPEPSIN


Mass: 10775.659 Da / Num. of mol.: 2 / Mutation: YES
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HUMAN IMMUNODEFICIENCY VIRUS / Strain: 99HHP1 (D10) / Variant: Z2/CDC-Z34 ISOLATE / Plasmid: PEXP5 / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21 / Variant (production host): AI / References: UniProt: P03366, HIV-1 retropepsin
#2: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Cl
#3: Chemical ChemComp-1T8 / methyl [(2S)-1-(2-{3-[(3R,6S,10Z)-3-hydroxy-4,7-dioxo-6-(propan-2-yl)-5,8-diazabicyclo[11.2.2]heptadeca-1(15),10,13,16-tetraen-3-yl]propyl}-2-[4-(pyridin-3-yl)benzyl]hydrazinyl)-3,3-dimethyl-1-oxobutan-2-yl]carbamate


Mass: 726.904 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C41H54N6O6
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 272 / 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: 54.41 % / Description: NONE

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: MAX II / Beamline: I911-3 / Wavelength: 0.91
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Jun 6, 2013 / Details: MIRRORS
RadiationMonochromator: SI / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.91 Å / Relative weight: 1
ReflectionResolution: 1.55→29.09 Å / Num. obs: 33883 / % possible obs: 98.1 % / Observed criterion σ(I): 6.8 / Redundancy: 11 % / Rmerge(I) obs: 0.09 / Net I/σ(I): 6.8
Reflection shellResolution: 1.55→1.63 Å / Redundancy: 10.4 % / Rmerge(I) obs: 0.43 / Mean I/σ(I) obs: 1.8 / % possible all: 96.4

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Processing

Software
NameVersionClassification
REFMAC5.8.0049refinement
iMOSFLMdata reduction
SCALAdata scaling
REFMACphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: NON-PUBLISHED

Resolution: 1.55→29.08 Å / Cor.coef. Fo:Fc: 0.954 / Cor.coef. Fo:Fc free: 0.945 / SU B: 1.298 / SU ML: 0.048 / Cross valid method: THROUGHOUT / ESU R: 0.077 / ESU R Free: 0.077 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS. U VALUES REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.20154 1738 5.1 %RANDOM
Rwork0.17619 ---
obs0.1775 32121 97.76 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 14.206 Å2
Baniso -1Baniso -2Baniso -3
1-0.18 Å20 Å20 Å2
2---0.18 Å20 Å2
3----0.01 Å2
Refinement stepCycle: LAST / Resolution: 1.55→29.08 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1512 0 56 272 1840
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0050.021619
X-RAY DIFFRACTIONr_bond_other_d00.021644
X-RAY DIFFRACTIONr_angle_refined_deg0.9062.0212207
X-RAY DIFFRACTIONr_angle_other_deg1.0913.013792
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.8255205
X-RAY DIFFRACTIONr_dihedral_angle_2_deg40.31824.90955
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.42515283
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.172158
X-RAY DIFFRACTIONr_chiral_restr0.4210.2259
X-RAY DIFFRACTIONr_gen_planes_refined0.0160.0211788
X-RAY DIFFRACTIONr_gen_planes_other0.0040.02337
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.5510.979804
X-RAY DIFFRACTIONr_mcbond_other1.5510.98805
X-RAY DIFFRACTIONr_mcangle_it2.2431.461002
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it3.8371.43815
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.549→1.589 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.261 132 -
Rwork0.22 2226 -
obs--95.23 %

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