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- PDB-4c4i: Structure-based design of orally bioavailable pyrrolopyridine inh... -

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Basic information

Entry
Database: PDB / ID: 4c4i
TitleStructure-based design of orally bioavailable pyrrolopyridine inhibitors of the mitotic kinase MPS1
ComponentsDUAL SPECIFICITY PROTEIN KINASE TTK
KeywordsTRANSFERASE / MITOSIS / STRUCTURE-BASED DRUG DESIGN
Function / homology
Function and homology information


protein localization to meiotic spindle midzone / meiotic spindle assembly checkpoint signaling / repair of mitotic kinetochore microtubule attachment defect / kinetochore binding / female meiosis chromosome segregation / protein localization to kinetochore / dual-specificity kinase / spindle organization / mitotic spindle assembly checkpoint signaling / protein serine/threonine/tyrosine kinase activity ...protein localization to meiotic spindle midzone / meiotic spindle assembly checkpoint signaling / repair of mitotic kinetochore microtubule attachment defect / kinetochore binding / female meiosis chromosome segregation / protein localization to kinetochore / dual-specificity kinase / spindle organization / mitotic spindle assembly checkpoint signaling / protein serine/threonine/tyrosine kinase activity / mitotic spindle organization / chromosome segregation / kinetochore / spindle / protein tyrosine kinase activity / protein serine kinase activity / protein serine/threonine kinase activity / positive regulation of cell population proliferation / ATP binding / identical protein binding / membrane / nucleus / cytoplasm
Similarity search - Function
Protein kinase Mps1 family / Tetratricopeptide-like helical domain superfamily / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain ...Protein kinase Mps1 family / Tetratricopeptide-like helical domain superfamily / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-7PE / Chem-X20 / Dual specificity protein kinase TTK
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.65 Å
AuthorsNaud, S. / Westwood, I.M. / Faisal, A. / Sheldrake, P. / Bavetsias, V. / Atrash, B. / Liu, M. / Hayes, A. / Schmitt, J. / Wood, A. ...Naud, S. / Westwood, I.M. / Faisal, A. / Sheldrake, P. / Bavetsias, V. / Atrash, B. / Liu, M. / Hayes, A. / Schmitt, J. / Wood, A. / Choi, V. / Boxall, K. / Mak, G. / Gurden, M. / Valenti, M. / de Haven Brandon, A. / Henley, A. / Baker, R. / McAndrew, C. / Matijssen, B. / Burke, R. / Eccles, S.A. / Raynaud, F.I. / Linardopoulos, S. / van Montfort, R. / Blagg, J.
CitationJournal: J.Med.Chem. / Year: 2013
Title: Structure-Based Design of Orally Bioavailable 1H-Pyrrolo[3, 2-C]Pyridine Inhibitors of the Mitotic Kinase Monopolar Spindle 1 (Mps1).
Authors: Naud, S. / Westwood, I.M. / Faisal, A. / Sheldrake, P.W. / Bavetsias, V. / Atrash, B. / Cheung, K.J. / Liu, M. / Hayes, A. / Schmitt, J. / Wood, A. / Choi, V. / Boxall, K. / Mak, G. / ...Authors: Naud, S. / Westwood, I.M. / Faisal, A. / Sheldrake, P.W. / Bavetsias, V. / Atrash, B. / Cheung, K.J. / Liu, M. / Hayes, A. / Schmitt, J. / Wood, A. / Choi, V. / Boxall, K. / Mak, G. / Gurden, M. / Valenti, M. / De-Haven-Brandon, A. / Henley, A. / Baker, R. / Mcandrew, C. / Matijssen, B. / Burke, R. / Hoelder, S. / Eccles, S.A. / Raynaud, F.I. / Linardopoulos, S. / Van Montfort, R.L.M. / Blagg, J.
History
DepositionSep 5, 2013Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 4, 2013Provider: repository / Type: Initial release
Revision 1.1Jan 15, 2014Group: Database references
Revision 1.2Dec 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: DUAL SPECIFICITY PROTEIN KINASE TTK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,9083
Polymers36,1151
Non-polymers7922
Water181
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)69.770, 105.220, 112.250
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number23
Space group name H-MI222

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Components

#1: Protein DUAL SPECIFICITY PROTEIN KINASE TTK / PHOSPHOTYROSINE PICKED THREONINE-PROTEIN KINASE / PYT / MONOPOLAR SPINDLE KINASE 1


Mass: 36115.258 Da / Num. of mol.: 1 / Fragment: KINASE DOMAIN, RESIDUES 519-808
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21 / Variant (production host): AI / References: UniProt: P33981, dual-specificity kinase
#2: Chemical ChemComp-X20 / tert-butyl 6-{[2-chloro-4-(dimethylcarbamoyl)phenyl]amino}-2-(1,3-oxazol-5-yl)-1H-pyrrolo[3,2-c]pyridine-1-carboxylate


Mass: 481.931 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H24ClN5O4
#3: Chemical ChemComp-7PE / 2-(2-(2-(2-(2-(2-ETHOXYETHOXY)ETHOXY)ETHOXY)ETHOXY)ETHOXY)ETHANOL / POLYETHYLENE GLYCOL FRAGMENT


Mass: 310.384 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H30O7
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: H2O
Sequence detailsTHE SEQUENCE INCLUDING HEXAHISTIDINE TAG IS AS DESCRIBED IN NAT. CHEM. BIOL. 2010, 6, 259-368.

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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: 3.5 Å3/Da / Density % sol: 64.9 % / Description: NONE
Crystal growpH: 7.5 / Details: 30-35% AQUEOUS PEG300 ONLY, pH 7.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04-1 / Wavelength: 0.9173
DetectorType: DECTRIS PILATUS / Detector: PIXEL / Date: Jul 31, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9173 Å / Relative weight: 1
ReflectionResolution: 2.65→39.34 Å / Num. obs: 12262 / % possible obs: 99.4 % / Observed criterion σ(I): 1.5 / Redundancy: 5.1 % / Biso Wilson estimate: 89.12 Å2 / Rmerge(I) obs: 0.06 / Net I/σ(I): 12.3
Reflection shellResolution: 2.65→2.78 Å / Redundancy: 5.1 % / Rmerge(I) obs: 0.82 / Mean I/σ(I) obs: 1.6 / % possible all: 99.6

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Processing

Software
NameVersionClassification
BUSTER2.11.4refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 4BI1

4bi1


Resolution: 2.65→21.43 Å / Cor.coef. Fo:Fc: 0.9441 / Cor.coef. Fo:Fc free: 0.9352 / SU R Cruickshank DPI: 0.35 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.339 / SU Rfree Blow DPI: 0.224 / SU Rfree Cruickshank DPI: 0.229
RfactorNum. reflection% reflectionSelection details
Rfree0.2135 594 4.86 %RANDOM
Rwork0.1913 ---
obs0.1924 12233 99.28 %-
Displacement parametersBiso mean: 83.56 Å2
Baniso -1Baniso -2Baniso -3
1-14.2034 Å20 Å20 Å2
2---16.5188 Å20 Å2
3---2.3154 Å2
Refine analyzeLuzzati coordinate error obs: 0.385 Å
Refinement stepCycle: LAST / Resolution: 2.65→21.43 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1964 0 41 1 2006
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.012052HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.132797HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d675SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes50HARMONIC2
X-RAY DIFFRACTIONt_gen_planes320HARMONIC5
X-RAY DIFFRACTIONt_it2052HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.84
X-RAY DIFFRACTIONt_other_torsion21.46
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion277SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact2293SEMIHARMONIC4
LS refinement shellResolution: 2.65→2.9 Å / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.2538 135 4.72 %
Rwork0.2204 2726 -
all0.222 2861 -
obs--99.28 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
17.79680.79831.48882.12610.23876.2852-0.2049-0.54440.46360.2185-0.12790.03190.0656-0.54970.33270.246-0.0258-0.01490.452-0.08220.2061-9.1234-23.0702-14.8212
25.18791.9575-1.59021.5934-0.34143.459-0.0853-0.58060.13340.291-0.0261-0.13830.01290.17810.11140.16380.0816-0.10290.389-0.0580.13386.7604-18.0803-18.9649
31.9015-1.85810.6623.89330.48122.85790.06020.15640.716-0.137-0.0353-0.5501-0.36270.2715-0.02490.2364-0.0296-0.00690.49380.00310.471513.4285-8.4019-30.8331
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{ A|516 - A|596 }
2X-RAY DIFFRACTION2{ A|597 - A|662 }
3X-RAY DIFFRACTION3{ A|663 - A|794 }

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