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- PDB-2xpa: DISCOVERY OF CELL-ACTIVE PHENYL-IMIDAZOLE PIN1 INHIBITORS BY STRU... -

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Basic information

Entry
Database: PDB / ID: 2xpa
TitleDISCOVERY OF CELL-ACTIVE PHENYL-IMIDAZOLE PIN1 INHIBITORS BY STRUCTURE-GUIDED FRAGMENT EVOLUTION
ComponentsPEPTIDYL-PROLYL CIS-TRANS ISOMERASE NIMA-INTERACTING 1
KeywordsISOMERASE / ROTAMASE / PROLINE DIRECTED KINASE / CELL CYCLE / ONCOGENIC TRANSFORMATION
Function / homology
Function and homology information


cis-trans isomerase activity / phosphothreonine residue binding / negative regulation of cell motility / ubiquitin ligase activator activity / regulation of protein localization to nucleus / GTPase activating protein binding / mitogen-activated protein kinase kinase binding / protein targeting to mitochondrion / protein peptidyl-prolyl isomerization / regulation of mitotic nuclear division ...cis-trans isomerase activity / phosphothreonine residue binding / negative regulation of cell motility / ubiquitin ligase activator activity / regulation of protein localization to nucleus / GTPase activating protein binding / mitogen-activated protein kinase kinase binding / protein targeting to mitochondrion / protein peptidyl-prolyl isomerization / regulation of mitotic nuclear division / negative regulation of SMAD protein signal transduction / PI5P Regulates TP53 Acetylation / negative regulation of amyloid-beta formation / cytoskeletal motor activity / RHO GTPases Activate NADPH Oxidases / phosphoserine residue binding / postsynaptic cytosol / negative regulation of protein binding / Rho protein signal transduction / regulation of cytokinesis / peptidylprolyl isomerase / Negative regulators of DDX58/IFIH1 signaling / peptidyl-prolyl cis-trans isomerase activity / phosphoprotein binding / negative regulation of transforming growth factor beta receptor signaling pathway / synapse organization / beta-catenin binding / negative regulation of protein catabolic process / regulation of protein stability / negative regulation of ERK1 and ERK2 cascade / ISG15 antiviral mechanism / tau protein binding / positive regulation of protein phosphorylation / neuron differentiation / positive regulation of canonical Wnt signaling pathway / regulation of gene expression / midbody / cellular response to hypoxia / Regulation of TP53 Activity through Phosphorylation / response to hypoxia / protein stabilization / nuclear speck / ciliary basal body / glutamatergic synapse / positive regulation of transcription by RNA polymerase II / nucleoplasm / nucleus / cytoplasm / cytosol
Similarity search - Function
Ubiquitin Ligase Nedd4; Chain: W; - #10 / Ubiquitin Ligase Nedd4; Chain: W; / : / Peptidyl-prolyl cis-trans isomerase, PpiC-type, conserved site / PpiC-type peptidyl-prolyl cis-trans isomerase signature. / PPIC-type PPIASE domain / PpiC-type peptidyl-prolyl cis-trans isomerase family profile. / Peptidyl-prolyl cis-trans isomerase, PpiC-type / Chitinase A; domain 3 - #40 / Chitinase A; domain 3 ...Ubiquitin Ligase Nedd4; Chain: W; - #10 / Ubiquitin Ligase Nedd4; Chain: W; / : / Peptidyl-prolyl cis-trans isomerase, PpiC-type, conserved site / PpiC-type peptidyl-prolyl cis-trans isomerase signature. / PPIC-type PPIASE domain / PpiC-type peptidyl-prolyl cis-trans isomerase family profile. / Peptidyl-prolyl cis-trans isomerase, PpiC-type / Chitinase A; domain 3 - #40 / Chitinase A; domain 3 / WW domain / WW/rsp5/WWP domain signature. / WW domain superfamily / WW/rsp5/WWP domain profile. / Domain with 2 conserved Trp (W) residues / WW domain / Peptidyl-prolyl cis-trans isomerase domain superfamily / Single Sheet / Roll / Mainly Beta / Alpha Beta
Similarity search - Domain/homology
Chem-4G5 / Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.9 Å
AuthorsPotter, A. / Oldfield, V. / Nunns, C. / Fromont, C. / Ray, S. / Northfield, C.J. / Bryant, C.J. / Scrace, S.F. / Robinson, D. / Matossova, N. ...Potter, A. / Oldfield, V. / Nunns, C. / Fromont, C. / Ray, S. / Northfield, C.J. / Bryant, C.J. / Scrace, S.F. / Robinson, D. / Matossova, N. / Baker, L. / Dokurno, P. / Surgenor, A.E. / Davis, B.E. / Richardson, C.M. / Murray, J.B. / Moore, J.D.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2010
Title: Discovery of Cell-Active Phenyl-Imidazole Pin1 Inhibitors by Structure-Guided Fragment Evolution.
Authors: Potter, A. / Oldfield, V. / Nunns, C. / Fromont, C. / Ray, S. / Northfield, C.J. / Bryant, C.J. / Scrace, S.F. / Robinson, D. / Matossova, N. / Baker, L. / Dokurno, P. / Surgenor, A.E. / ...Authors: Potter, A. / Oldfield, V. / Nunns, C. / Fromont, C. / Ray, S. / Northfield, C.J. / Bryant, C.J. / Scrace, S.F. / Robinson, D. / Matossova, N. / Baker, L. / Dokurno, P. / Surgenor, A.E. / Davis, B. / Richardson, C.M. / Murray, J.B. / Moore, J.D.
History
DepositionAug 25, 2010Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 12, 2011Provider: repository / Type: Initial release
Revision 1.1May 8, 2011Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Jan 30, 2019Group: Data collection / Experimental preparation / Other
Category: exptl_crystal_grow / pdbx_database_proc / pdbx_database_status
Item: _exptl_crystal_grow.method / _pdbx_database_status.recvd_author_approval
Revision 1.4Feb 6, 2019Group: Data collection / Experimental preparation / Category: exptl_crystal_grow / Item: _exptl_crystal_grow.temp
Revision 1.5Dec 20, 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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: PEPTIDYL-PROLYL CIS-TRANS ISOMERASE NIMA-INTERACTING 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)19,3733
Polymers18,5251
Non-polymers8492
Water1,946108
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)68.367, 68.367, 79.351
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number152
Space group name H-MP3121

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Components

#1: Protein PEPTIDYL-PROLYL CIS-TRANS ISOMERASE NIMA-INTERACTING 1 / PEPTIDYL-PROLYL CIS-TRANS ISOMERASE PIN1 / PIN1 / PPIASE PIN1 / ROTAMASE PIN1


Mass: 18524.525 Da / Num. of mol.: 1 / Mutation: YES
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Plasmid: PET28A / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: Q13526, peptidylprolyl isomerase
#2: Chemical ChemComp-12P / DODECAETHYLENE GLYCOL / POLYETHYLENE GLYCOL PEG400


Mass: 546.646 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H50O13 / Comment: precipitant*YM
#3: Chemical ChemComp-4G5 / 4-[(2-amino-2-oxoethyl)(methyl)carbamoyl]-2-phenyl-1H-imidazole-5-carboxylic acid


Mass: 302.285 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H14N4O4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 108 / Source method: isolated from a natural source / Formula: H2O
Compound detailsENGINEERED RESIDUE IN CHAIN A, ARG 14 TO ALA

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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: 2.87 Å3/Da / Density % sol: 57 % / Description: NONE
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 2.2M AMMONIUM SULPHATE, 0.1M HEPES BUFFER, 1% PEG 400, 5MM DTT, PH 7.5, VAPOR DIFFUSION, HANGING DROP, TEMPERATURE 277.0K

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Data collection

DiffractionMean temperature: 277 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RUH3R / Wavelength: 1.5418
DetectorType: RIGAKU IMAGE PLATE / Detector: IMAGE PLATE / Details: MIRRORS
RadiationMonochromator: CU FILTER / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.9→30 Å / Num. obs: 16724 / % possible obs: 96.4 % / Observed criterion σ(I): 2 / Redundancy: 2.07 % / Rmerge(I) obs: 0.05 / Net I/σ(I): 8.9
Reflection shellHighest resolution: 1.9 Å / Redundancy: 1.93 % / Rmerge(I) obs: 0.33 / Mean I/σ(I) obs: 2.1 / % possible all: 90.1

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Processing

Software
NameVersionClassification
REFMAC5.5.0109refinement
d*TREKdata reduction
d*TREKdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 3KCE

3kce


Resolution: 1.9→59.23 Å / Cor.coef. Fo:Fc: 0.953 / Cor.coef. Fo:Fc free: 0.929 / SU B: 3.434 / SU ML: 0.1 / Cross valid method: THROUGHOUT / ESU R: 0.142 / ESU R Free: 0.145 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.25696 846 5.1 %RANDOM
Rwork0.20666 ---
obs0.20905 15864 96.32 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 31.344 Å2
Baniso -1Baniso -2Baniso -3
1-0.9 Å20.45 Å20 Å2
2--0.9 Å20 Å2
3----1.35 Å2
Refinement stepCycle: LAST / Resolution: 1.9→59.23 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1160 0 39 108 1307
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0240.0211233
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg2.011.9711651
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.0055146
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.01822.37359
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.62115214
X-RAY DIFFRACTIONr_dihedral_angle_4_deg22.5521514
X-RAY DIFFRACTIONr_chiral_restr0.1440.2163
X-RAY DIFFRACTIONr_gen_planes_refined0.0110.021950
X-RAY DIFFRACTIONr_gen_planes_other
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_it1.3631.5728
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it2.36721166
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it3.493505
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it5.8014.5484
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: 1.9→1.949 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.433 52 -
Rwork0.327 1051 -
obs--88.95 %

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