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

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Basic information

Entry
Database: PDB / ID: 3kaf
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 / postsynaptic cytosol / mitogen-activated protein kinase kinase binding / regulation of mitotic nuclear division / 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 / postsynaptic cytosol / mitogen-activated protein kinase kinase binding / 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 / protein peptidyl-prolyl isomerization / positive regulation of protein dephosphorylation / ciliary basal body / negative regulation of protein binding / regulation of cytokinesis / peptidylprolyl isomerase / peptidyl-prolyl cis-trans isomerase activity / Negative regulators of DDX58/IFIH1 signaling / synapse organization / phosphoprotein binding / negative regulation of transforming growth factor beta receptor signaling pathway / regulation of protein phosphorylation / regulation of protein stability / tau protein binding / negative regulation of ERK1 and ERK2 cascade / negative regulation of protein catabolic process / neuron differentiation / ISG15 antiviral mechanism / beta-catenin binding / positive regulation of GTPase activity / 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 / cell cycle / 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 / WW/rsp5/WWP domain signature. ...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. / WW domain superfamily / WW/rsp5/WWP domain profile. / Domain with 2 conserved Trp (W) residues / Chitinase A; domain 3 / WW domain / Peptidyl-prolyl cis-trans isomerase domain superfamily / Single Sheet / Roll / Mainly Beta / Alpha Beta
Similarity search - Domain/homology
Chem-4D9 / Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MIR / Resolution: 2.3 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)18,8332
Polymers18,4671
Non-polymers3651
Water86548
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)67.937, 67.937, 79.247
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: 18467.475 Da / Num. of mol.: 1 / Mutation: R14A, Q131A
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-4D9 / 3-(1H-benzimidazol-2-yl)-N-(1-benzothiophen-2-ylcarbonyl)-D-alanine / (R)-2-[(Benzo[b]thiophene-2-carbonyl)-amino]-3-(1H-benzoimidazol-2-yl)-propionic acid


Mass: 365.406 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H15N3O3S
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 48 / 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: 2.86 Å3/Da / Density % sol: 56.97 %
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: Nov 3, 2006 / 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: 2.3→27.6 Å / Num. all: 9395 / Num. obs: 9395 / % possible obs: 96.2 % / Observed criterion σ(F): 1 / Observed criterion σ(I): 1 / Redundancy: 2.9 % / Rmerge(I) obs: 0.081 / Net I/σ(I): 4.6
Reflection shellResolution: 2.3→2.38 Å / Redundancy: 2.8 % / Rmerge(I) obs: 0.438 / Mean I/σ(I) obs: 1.3 / Num. unique all: 885 / % possible all: 99.8

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Processing

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

1pin


Resolution: 2.3→27.6 Å / Cor.coef. Fo:Fc: 0.945 / Cor.coef. Fo:Fc free: 0.898 / SU B: 9.04 / SU ML: 0.213 / Cross valid method: THROUGHOUT / ESU R: 0.296 / ESU R Free: 0.274 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.31195 452 4.8 %RANDOM
Rwork0.22664 ---
obs0.23048 8939 96.05 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 46.677 Å2
Baniso -1Baniso -2Baniso -3
1-2.26 Å21.13 Å20 Å2
2--2.26 Å20 Å2
3----3.39 Å2
Refinement stepCycle: LAST / Resolution: 2.3→27.6 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1152 0 26 48 1226
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0190.0211204
X-RAY DIFFRACTIONr_angle_refined_deg1.9081.9721620
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.5275143
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.74422.45657
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.60915207
X-RAY DIFFRACTIONr_dihedral_angle_4_deg24.3821513
X-RAY DIFFRACTIONr_chiral_restr0.1170.2163
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.021932
X-RAY DIFFRACTIONr_mcbond_it1.0941.5721
X-RAY DIFFRACTIONr_mcangle_it1.98321154
X-RAY DIFFRACTIONr_scbond_it2.63483
X-RAY DIFFRACTIONr_scangle_it4.1574.5466
LS refinement shellResolution: 2.3→2.36 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.394 36 -
Rwork0.355 674 -
obs-710 99.72 %

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