[English] 日本語
Yorodumi
- PDB-5f4n: Multi-parameter lead optimization to give an oral CHK1 inhibitor ... -

+
Open data


ID or keywords:

Loading...

-
Basic information

Entry
Database: PDB / ID: 5f4n
TitleMulti-parameter lead optimization to give an oral CHK1 inhibitor clinical candidate: (R)-5-((4-((morpholin-2-ylmethyl)amino)-5-(trifluoromethyl)pyridin-2-yl)amino)pyrazine-2-carbonitrile (CCT245737)
ComponentsSerine/threonine-protein kinase Chk1
KeywordsTRANSFERASE / Inhibitor DNA-damage CHK1-potency HERG-activity
Function / homology
Function and homology information


negative regulation of G0 to G1 transition / apoptotic process involved in development / histone H3T11 kinase activity / negative regulation of DNA biosynthetic process / negative regulation of mitotic nuclear division / mitotic G2/M transition checkpoint / regulation of mitotic centrosome separation / nucleus organization / inner cell mass cell proliferation / negative regulation of gene expression, epigenetic ...negative regulation of G0 to G1 transition / apoptotic process involved in development / histone H3T11 kinase activity / negative regulation of DNA biosynthetic process / negative regulation of mitotic nuclear division / mitotic G2/M transition checkpoint / regulation of mitotic centrosome separation / nucleus organization / inner cell mass cell proliferation / negative regulation of gene expression, epigenetic / regulation of double-strand break repair via homologous recombination / cellular response to caffeine / Transcriptional Regulation by E2F6 / mitotic G2 DNA damage checkpoint signaling / Presynaptic phase of homologous DNA pairing and strand exchange / replicative senescence / Activation of ATR in response to replication stress / Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex / positive regulation of cell cycle / signal transduction in response to DNA damage / replication fork / DNA damage checkpoint signaling / condensed nuclear chromosome / regulation of signal transduction by p53 class mediator / Ubiquitin Mediated Degradation of Phosphorylated Cdc25A / TP53 Regulates Transcription of DNA Repair Genes / peptidyl-threonine phosphorylation / G2/M DNA damage checkpoint / Signaling by SCF-KIT / cellular response to mechanical stimulus / G2/M transition of mitotic cell cycle / regulation of cell population proliferation / Processing of DNA double-strand break ends / Regulation of TP53 Activity through Phosphorylation / DNA replication / non-specific serine/threonine protein kinase / protein kinase activity / intracellular signal transduction / chromatin remodeling / protein domain specific binding / protein phosphorylation / protein serine kinase activity / DNA repair / intracellular membrane-bounded organelle / protein serine/threonine kinase activity / centrosome / apoptotic process / DNA damage response / chromatin / protein-containing complex / extracellular space / nucleoplasm / ATP binding / nucleus / cytosol / cytoplasm
Similarity search - Function
Checkpoint kinase 1, catalytic domain / 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 ...Checkpoint kinase 1, catalytic domain / 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-5UY / Serine/threonine-protein kinase Chk1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.91 Å
AuthorsCollins, I. / Garrett, M.D. / van Montfort, R. / Osborne, J.D. / Matthews, T.P. / McHardy, T. / Proisy, N. / Cheung, K.J. / Lainchbury, M. / Brown, N. ...Collins, I. / Garrett, M.D. / van Montfort, R. / Osborne, J.D. / Matthews, T.P. / McHardy, T. / Proisy, N. / Cheung, K.J. / Lainchbury, M. / Brown, N. / Walton, M.I. / Eve, P.D. / Boxall, K.J. / Hayes, A. / Henley, A.T. / Valenti, M.R. / De Haven Brandon, A.K. / Box, G. / Westwood, I.M. / Jamin, Y. / Robinson, S.P. / Leonard, P. / Reader, J.C. / Aherne, G.W. / Raynaud, F.I. / Eccles, S.A.
CitationJournal: J.Med.Chem. / Year: 2016
Title: Multiparameter Lead Optimization to Give an Oral Checkpoint Kinase 1 (CHK1) Inhibitor Clinical Candidate: (R)-5-((4-((Morpholin-2-ylmethyl)amino)-5-(trifluoromethyl)pyridin-2-yl)amino)pyrazine- ...Title: Multiparameter Lead Optimization to Give an Oral Checkpoint Kinase 1 (CHK1) Inhibitor Clinical Candidate: (R)-5-((4-((Morpholin-2-ylmethyl)amino)-5-(trifluoromethyl)pyridin-2-yl)amino)pyrazine-2-carbonitrile (CCT245737).
Authors: Osborne, J.D. / Matthews, T.P. / McHardy, T. / Proisy, N. / Cheung, K.M. / Lainchbury, M. / Brown, N. / Walton, M.I. / Eve, P.D. / Boxall, K.J. / Hayes, A. / Henley, A.T. / Valenti, M.R. / ...Authors: Osborne, J.D. / Matthews, T.P. / McHardy, T. / Proisy, N. / Cheung, K.M. / Lainchbury, M. / Brown, N. / Walton, M.I. / Eve, P.D. / Boxall, K.J. / Hayes, A. / Henley, A.T. / Valenti, M.R. / De Haven Brandon, A.K. / Box, G. / Jamin, Y. / Robinson, S.P. / Westwood, I.M. / van Montfort, R.L. / Leonard, P.M. / Lamers, M.B. / Reader, J.C. / Aherne, G.W. / Raynaud, F.I. / Eccles, S.A. / Garrett, M.D. / Collins, I.
History
DepositionDec 3, 2015Deposition site: RCSB / Processing site: PDBE
Revision 1.0May 25, 2016Provider: repository / Type: Initial release
Revision 1.1Jun 22, 2016Group: Database references

-
Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

-
Assembly

Deposited unit
A: Serine/threonine-protein kinase Chk1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,6289
Polymers31,4571
Non-polymers1,1718
Water5,639313
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1220 Å2
ΔGint10 kcal/mol
Surface area12640 Å2
MethodPISA
Unit cell
Length a, b, c (Å)44.970, 65.870, 57.900
Angle α, β, γ (deg.)90.00, 94.69, 90.00
Int Tables number4
Space group name H-MP1211

-
Components

#1: Protein Serine/threonine-protein kinase Chk1 / CHK1 checkpoint homolog / Cell cycle checkpoint kinase / Checkpoint kinase-1


Mass: 31457.248 Da / Num. of mol.: 1 / Source method: obtained synthetically
Details: methyl 6-[(5-cyanopyrazin-2-yl)amino]-4-[(morpholin-2-ylmethyl)amino]pyridine-3-carboxylate
Source: (synth.) Homo sapiens (human)
References: UniProt: O14757, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-5UY / methyl 6-[(5-cyanopyrazin-2-yl)amino]-4-[[(2~{R})-morpholin-2-yl]methylamino]pyridine-3-carboxylate


Mass: 369.378 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C17H19N7O3
#3: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C2H6O2
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 313 / Source method: isolated from a natural source / Formula: H2O

-
Experimental details

-
Experiment

ExperimentMethod: X-RAY DIFFRACTION

-
Sample preparation

CrystalDensity Matthews: 2.72 Å3/Da / Density % sol: 54.73 %
Crystal growTemperature: 291.15 K / Method: vapor diffusion, sitting drop / Details: PEG3350 DL-malic acid

-
Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 HF / Wavelength: 1.54 Å
DetectorType: RIGAKU SATURN 944 / Detector: CCD / Date: Jan 30, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 1.91→26.54 Å / Num. obs: 21594 / % possible obs: 82.4 % / Redundancy: 2.8 % / Biso Wilson estimate: 22.35 Å2 / Net I/σ(I): 10.9

-
Processing

Software
NameVersionClassification
BUSTER2.10.2refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.91→26.54 Å / Cor.coef. Fo:Fc: 0.9581 / Cor.coef. Fo:Fc free: 0.9363 / SU R Cruickshank DPI: 0.138 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.152 / SU Rfree Blow DPI: 0.135 / SU Rfree Cruickshank DPI: 0.129
RfactorNum. reflection% reflectionSelection details
Rfree0.1883 1040 4.82 %RANDOM
Rwork0.1489 ---
obs0.1507 21580 82.23 %-
Displacement parametersBiso mean: 27.42 Å2
Baniso -1Baniso -2Baniso -3
1-0.4617 Å20 Å2-0.1219 Å2
2---2.1497 Å20 Å2
3---1.6879 Å2
Refine analyzeLuzzati coordinate error obs: 0.179 Å
Refinement stepCycle: 1 / Resolution: 1.91→26.54 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2064 0 72 313 2449
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.012186HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.982961HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d748SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes51HARMONIC2
X-RAY DIFFRACTIONt_gen_planes347HARMONIC5
X-RAY DIFFRACTIONt_it2186HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.11
X-RAY DIFFRACTIONt_other_torsion15.13
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion272SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies7HARMONIC1
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact2834SEMIHARMONIC4
LS refinement shellResolution: 1.91→2 Å / Total num. of bins used: 11
RfactorNum. reflection% reflection
Rfree0.2001 45 4.6 %
Rwork0.1985 934 -
all0.1986 979 -
obs--28.12 %
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)
10.1593-1.3602-0.799901.31673.9388-0.00510.2717-0.0037-0.036-0.01440.24540.4425-0.21880.01950.0652-0.0669-0.01950.0689-0.0474-0.10689.071-2.42874.0277
22.47740.4655-0.36011.3901-0.04811.1065-0.05830.0095-0.1119-0.0772-0.0054-0.03880.0506-0.03460.0636-0.07810.01080.0006-0.1050.0019-0.068915.6062.506227.0182
3-0.07372.47060.38794.9768-1.86311.4967-0.0226-0.01370.36520.0982-0.1673-0.1212-0.1214-0.05050.1899-0.04140.016-0.0017-0.0684-0.01850.057122.461717.86130.3574
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{A|3 - 61}
2X-RAY DIFFRACTION2{A|62 - 255}
3X-RAY DIFFRACTION3{A|256 - 271}

+
About Yorodumi

-
News

-
Feb 9, 2022. New format data for meta-information of EMDB entries

New format data for meta-information of EMDB entries

  • Version 3 of the EMDB header file is now the official format.
  • The previous official version 1.9 will be removed from the archive.

Related info.:EMDB header

External links:wwPDB to switch to version 3 of the EMDB data model

-
Aug 12, 2020. Covid-19 info

Covid-19 info

URL: https://pdbj.org/emnavi/covid19.php

New page: Covid-19 featured information page in EM Navigator.

Related info.:Covid-19 info / Mar 5, 2020. Novel coronavirus structure data

+
Mar 5, 2020. Novel coronavirus structure data

Novel coronavirus structure data

Related info.:Yorodumi Speices / Aug 12, 2020. Covid-19 info

External links:COVID-19 featured content - PDBj / Molecule of the Month (242)：Coronavirus Proteases

+
Jan 31, 2019. EMDB accession codes are about to change! (news from PDBe EMDB page)

EMDB accession codes are about to change! (news from PDBe EMDB page)

  • The allocation of 4 digits for EMDB accession codes will soon come to an end. Whilst these codes will remain in use, new EMDB accession codes will include an additional digit and will expand incrementally as the available range of codes is exhausted. The current 4-digit format prefixed with “EMD-” (i.e. EMD-XXXX) will advance to a 5-digit format (i.e. EMD-XXXXX), and so on. It is currently estimated that the 4-digit codes will be depleted around Spring 2019, at which point the 5-digit format will come into force.
  • The EM Navigator/Yorodumi systems omit the EMD- prefix.

Related info.:Q: What is EMD? / ID/Accession-code notation in Yorodumi/EM Navigator

External links:EMDB Accession Codes are Changing Soon! / Contact to PDBj

+
Jul 12, 2017. Major update of PDB

Major update of PDB

  • wwPDB released updated PDB data conforming to the new PDBx/mmCIF dictionary.
  • This is a major update changing the version number from 4 to 5, and with Remediation, in which all the entries are updated.
  • In this update, many items about electron microscopy experimental information are reorganized (e.g. em_software).
  • Now, EM Navigator and Yorodumi are based on the updated data.

External links:wwPDB Remediation / Enriched Model Files Conforming to OneDep Data Standards Now Available in the PDB FTP Archive

-
Yorodumi

Thousand views of thousand structures

  • Yorodumi is a browser for structure data from EMDB, PDB, SASBDB, etc.
  • This page is also the successor to EM Navigator detail page, and also detail information page/front-end page for Omokage search.
  • The word "yorodu" (or yorozu) is an old Japanese word meaning "ten thousand". "mi" (miru) is to see.

Related info.:EMDB / PDB / SASBDB / Comparison of 3 databanks / Yorodumi Search / Aug 31, 2016. New EM Navigator & Yorodumi / Yorodumi Papers / Jmol/JSmol / Function and homology information / Changes in new EM Navigator and Yorodumi

Read more