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- PDB-4c4g: Structure-based design of orally bioavailable pyrrolopyridine inh... -

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Basic information

Entry
Database: PDB / ID: 4c4g
TitleStructure-based design of orally bioavailable pyrrolopyridine inhibitors of the mitotic kinase MPS1
ComponentsDUAL SPECIFICITY PROTEIN KINASE TTK
KeywordsTRANSFERASE / PROTEIN KINASE / MITOSIS / STRUCTURE-BASED 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-7RO / 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_conn / 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_conn.pdbx_leaving_atom_flag / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.3Nov 13, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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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)37,4356
Polymers36,1951
Non-polymers1,2405
Water1448
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)70.930, 111.900, 112.680
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 / 2.7.12.1 / PHOSPHOTYROSINE PICKED THREONINE-PROTEIN KINASE / PYT / MONOPOLAR SPINDLE KINASE 1 / MPS1


Mass: 36195.234 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(DE3) / Variant (production host): AI / References: UniProt: P33981, dual-specificity kinase
#2: Chemical ChemComp-7RO / tert-butyl 6-((2-chloro-4-(dimethylcarbamoyl)phenyl)amino)-2-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridine-1-carboxylate


Mass: 494.973 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H27ClN6O3
#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.: 2 / Source method: obtained synthetically / Formula: C14H30O7
#4: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 8 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY
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: 3.8 Å3/Da / Density % sol: 68 % / 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: I03 / Wavelength: 0.9762
DetectorType: DECTRIS PILATUS / Detector: PIXEL / Date: Apr 18, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9762 Å / Relative weight: 1
ReflectionResolution: 2.65→41.04 Å / Num. obs: 13230 / % possible obs: 99.1 % / Observed criterion σ(I): 1.5 / Redundancy: 4.6 % / Biso Wilson estimate: 99.99 Å2 / Rmerge(I) obs: 0.04 / Net I/σ(I): 15.1
Reflection shellResolution: 2.65→2.78 Å / Redundancy: 4.3 % / Rmerge(I) obs: 1.15 / Mean I/σ(I) obs: 1.6 / % possible all: 96.8

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Processing

Software
NameVersionClassification
BUSTER-TNT2.11.4refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 4BI1

4bi1


Resolution: 2.65→41.04 Å / Cor.coef. Fo:Fc: 0.9494 / Cor.coef. Fo:Fc free: 0.937 / Cross valid method: THROUGHOUT / σ(F): 0
Details: THE LIGAND USED FOR SOAKING WAS 3- CHLORO-N,N-DIMETHYL-4-(2- (1-METHYL-1H-PYRAZOL-4-YL)-1H- PYRROLO(3,2-C)PYRIDIN-6- YLAMINO)BENZAMIDE BUT THE N-BOC PRECURSOR MODELLED HEREIN WAS DETECTED AS ...Details: THE LIGAND USED FOR SOAKING WAS 3- CHLORO-N,N-DIMETHYL-4-(2- (1-METHYL-1H-PYRAZOL-4-YL)-1H- PYRROLO(3,2-C)PYRIDIN-6- YLAMINO)BENZAMIDE BUT THE N-BOC PRECURSOR MODELLED HEREIN WAS DETECTED AS AN IMPURITY AT LESS THAN 2 PERCENT BY LCMS.
RfactorNum. reflection% reflectionSelection details
Rfree0.2231 632 4.8 %RANDOM
Rwork0.1926 ---
obs0.1941 13226 98.81 %-
Displacement parametersBiso mean: 103.05 Å2
Baniso -1Baniso -2Baniso -3
1-11.7705 Å20 Å20 Å2
2--4.6966 Å20 Å2
3----16.4671 Å2
Refine analyzeLuzzati coordinate error obs: 0.514 Å
Refinement stepCycle: LAST / Resolution: 2.65→41.04 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1951 0 57 8 2016
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.012052HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.152792HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d671SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes47HARMONIC2
X-RAY DIFFRACTIONt_gen_planes319HARMONIC5
X-RAY DIFFRACTIONt_it2052HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.83
X-RAY DIFFRACTIONt_other_torsion22.53
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion276SEMIHARMONIC5
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_contact2272SEMIHARMONIC4
LS refinement shellResolution: 2.65→2.86 Å / Total num. of bins used: 7
RfactorNum. reflection% reflection
Rfree0.2434 136 5.16 %
Rwork0.221 2500 -
all0.2221 2636 -
obs--98.81 %
Refinement TLS params.Method: refined / Origin x: 4.9899 Å / Origin y: 32.4446 Å / Origin z: 129.678 Å
111213212223313233
T-0.7523 Å2-0.0267 Å2-0.0073 Å2--0.6772 Å20.1664 Å2---0.3954 Å2
L6.8002 °2-1.5686 °2-0.8301 °2-3.6743 °2-0.7449 °2--1.8301 °2
S0.053 Å °0.7368 Å °0.3811 Å °-0.2252 Å °-0.1128 Å °-0.1645 Å °0.0733 Å °0.0491 Å °0.0597 Å °
Refinement TLS groupSelection details: CHAIN A

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