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- PDB-3kai: Structure-guided design of alpha-amino acid-derived Pin1 inhibitors -

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Basic information

Entry
Database: PDB / ID: 3kai
TitleStructure-guided design of alpha-amino acid-derived Pin1 inhibitors
ComponentsPeptidyl-prolyl cis-trans isomerase NIMA-interacting 1
KeywordsISOMERASE / SBDD / PPIASE / ROTAMASE / SMALL MOLECULE / Proline directed kinase / cell cycle / Oncogenic transformation / Nucleus / Phosphoprotein
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 / regulation of mitotic nuclear division / postsynaptic cytosol / negative regulation of SMAD protein signal transduction ...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 / regulation of mitotic nuclear division / postsynaptic cytosol / negative regulation of SMAD protein signal transduction / PI5P Regulates TP53 Acetylation / negative regulation of amyloid-beta formation / cytoskeletal motor activity / protein peptidyl-prolyl isomerization / phosphoserine residue binding / RHO GTPases Activate NADPH Oxidases / : / positive regulation of GTPase activity / ciliary basal body / regulation of cytokinesis / negative regulation of protein binding / 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 / regulation of protein phosphorylation / regulation of protein stability / tau protein binding / negative regulation of protein catabolic process / neuron differentiation / negative regulation of ERK1 and ERK2 cascade / ISG15 antiviral mechanism / beta-catenin binding / positive regulation of canonical Wnt signaling pathway / positive regulation of protein binding / midbody / regulation of gene expression / Regulation of TP53 Activity through Phosphorylation / response to hypoxia / protein stabilization / nuclear speck / positive regulation of protein phosphorylation / glutamatergic synapse / positive regulation of transcription by RNA polymerase II / nucleoplasm / nucleus / cytosol / cytoplasm
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 / WW domain ...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 / WW domain / WW/rsp5/WWP domain signature. / Chitinase A; domain 3 / 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-4FI / Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.9 Å
AuthorsBaker, L.M. / Dokurno, P. / Robinson, D.A. / Surgenor, A.E. / Murray, J.B. / Potter, A.J. / Moore, J.D.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2010
Title: Structure-guided design of alpha-amino acid-derived Pin1 inhibitors
Authors: Potter, A.J. / Ray, S. / Gueritz, L. / Nunns, C.L. / Bryant, C.J. / Scrace, S.F. / Matassova, N. / Baker, L.M. / Dokurno, P. / Robinson, D.A. / Surgenor, A.E. / Davis, B. / Murray, J.B. / ...Authors: Potter, A.J. / Ray, S. / Gueritz, L. / Nunns, C.L. / Bryant, C.J. / Scrace, S.F. / Matassova, N. / Baker, L.M. / Dokurno, P. / Robinson, D.A. / Surgenor, A.E. / Davis, B. / Murray, J.B. / Richardson, C.M. / Moore, J.D.
History
DepositionOct 19, 2009Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Dec 22, 2009Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Nov 10, 2021Group: Database references / Derived calculations / Category: database_2 / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.3Nov 1, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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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)19,4713
Polymers18,5251
Non-polymers9462
Water2,090116
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)68.640, 68.640, 79.233
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 / Rotamase Pin1 / PPIase Pin1


Mass: 18524.525 Da / Num. of mol.: 1 / Mutation: R14A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PIN1 / 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-4FI / (2R)-2-[(2-methyl-5-phenyl-pyrazol-3-yl)carbonylamino]-3-naphthalen-2-yl-propanoic acid


Mass: 399.442 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H21N3O3
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 116 / 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: 2.91 Å3/Da / Density % sol: 57.71 %
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 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RUH3R / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE / Date: Aug 21, 2007 / Details: mirrors
RadiationMonochromator: mirrors / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.9→59.44 Å / Num. all: 16782 / Num. obs: 16782 / % possible obs: 96.1 % / Observed criterion σ(F): 1 / Observed criterion σ(I): 1 / Redundancy: 2.1 % / Rmerge(I) obs: 0.06 / Net I/σ(I): 5.6
Reflection shellResolution: 1.9→1.97 Å / Redundancy: 2.1 % / Rmerge(I) obs: 0.353 / Mean I/σ(I) obs: 1.7 / Num. unique all: 1010 / % possible all: 85.3

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Processing

Software
NameVersionClassification
CrystalCleardata collection
AMoREphasing
REFMAC5.5.0072refinement
d*TREKdata reduction
d*TREKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1PIN

1pin


Resolution: 1.9→29.7 Å / Cor.coef. Fo:Fc: 0.956 / Cor.coef. Fo:Fc free: 0.934 / SU B: 3.823 / SU ML: 0.106 / Cross valid method: THROUGHOUT / ESU R: 0.143 / ESU R Free: 0.144 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.254 861 5.1 %RANDOM
Rwork0.20569 ---
obs0.20802 15921 96.01 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 32.684 Å2
Baniso -1Baniso -2Baniso -3
1-0.68 Å20.34 Å20 Å2
2--0.68 Å20 Å2
3----1.02 Å2
Refinement stepCycle: LAST / Resolution: 1.9→29.7 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1162 0 49 116 1327
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0260.0211239
X-RAY DIFFRACTIONr_angle_refined_deg2.121.9841660
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.1975145
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.73222.71259
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.04115213
X-RAY DIFFRACTIONr_dihedral_angle_4_deg23.6991513
X-RAY DIFFRACTIONr_chiral_restr0.1520.2164
X-RAY DIFFRACTIONr_gen_planes_refined0.010.021951
X-RAY DIFFRACTIONr_mcbond_it1.3261.5724
X-RAY DIFFRACTIONr_mcangle_it2.40121161
X-RAY DIFFRACTIONr_scbond_it3.8583515
X-RAY DIFFRACTIONr_scangle_it6.2914.5498
LS refinement shellResolution: 1.899→1.949 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.38 65 -
Rwork0.339 954 -
obs-1019 81.39 %

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