5OQ6

Structure of CHK1 12-pt. mutant complex with aminopyrimido-benzodiazepinone LRRK2 inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.95 Å
  • R-Value Free: 0.192 
  • R-Value Work: 0.158 
  • R-Value Observed: 0.160 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Design of Leucine-Rich Repeat Kinase 2 (LRRK2) Inhibitors Using a Crystallographic Surrogate Derived from Checkpoint Kinase 1 (CHK1).

Williamson, D.S.Smith, G.P.Acheson-Dossang, P.Bedford, S.T.Chell, V.Chen, I.J.Daechsel, J.C.A.Daniels, Z.David, L.Dokurno, P.Hentzer, M.Herzig, M.C.Hubbard, R.E.Moore, J.D.Murray, J.B.Newland, S.Ray, S.C.Shaw, T.Surgenor, A.E.Terry, L.Thirstrup, K.Wang, Y.Christensen, K.V.

(2017) J Med Chem 60: 8945-8962

  • DOI: https://doi.org/10.1021/acs.jmedchem.7b01186
  • Primary Citation of Related Structures:  
    5OOP, 5OOR, 5OOT, 5OP2, 5OP4, 5OP5, 5OP7, 5OPB, 5OPR, 5OPS, 5OPU, 5OPV, 5OQ5, 5OQ6, 5OQ7, 5OQ8

  • PubMed Abstract: 

    Mutations in leucine-rich repeat kinase 2 (LRRK2), such as G2019S, are associated with an increased risk of developing Parkinson's disease. Surrogates for the LRRK2 kinase domain based on checkpoint kinase 1 (CHK1) mutants were designed, expressed in insect cells infected with baculovirus, purified, and crystallized. X-ray structures of the surrogates complexed with known LRRK2 inhibitors rationalized compound potency and selectivity. The CHK1 10-point mutant was preferred, following assessment of surrogate binding affinity with LRRK2 inhibitors. Fragment hit-derived arylpyrrolo[2,3-b]pyridine LRRK2 inhibitors underwent structure-guided optimization using this crystallographic surrogate. LRRK2-pSer935 HEK293 IC 50 data for 22 were consistent with binding to Ala2016 in LRRK2 (equivalent to Ala147 in CHK1 10-point mutant structure). Compound 22 was shown to be potent, moderately selective, orally available, and brain-penetrant in wild-type mice, and confirmation of target engagement was demonstrated, with LRRK2-pSer935 IC 50 values for 22 in mouse brain and kidney being 1.3 and 5 nM, respectively.


  • Organizational Affiliation

    Vernalis (R&D) Ltd. , Granta Park, Great Abington, Cambridge, CB21 6GB, United Kingdom.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Serine/threonine-protein kinase Chk1297Homo sapiensMutation(s): 12 
Gene Names: CHEK1CHK1
EC: 2.7.11.1
UniProt & NIH Common Fund Data Resources
Find proteins for O14757 (Homo sapiens)
Explore O14757 
Go to UniProtKB:  O14757
PHAROS:  O14757
GTEx:  ENSG00000149554 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO14757
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
4K4 (Subject of Investigation/LOI)
Query on 4K4

Download Ideal Coordinates CCD File 
B [auth A]2-[(2-methoxy-4-{[4-(4-methylpiperazin-1-yl)piperidin-1-yl]carbonyl}phenyl)amino]-5,11-dimethyl-5,11-dihydro-6H-pyrimido[4,5-b][1,4]benzodiazepin-6-one
C31 H38 N8 O3
IWMCPJZTADUIFX-UHFFFAOYSA-N
CL
Query on CL

Download Ideal Coordinates CCD File 
C [auth A]CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
Binding Affinity Annotations 
IDSourceBinding Affinity
4K4 Binding MOAD:  5OQ6 Ki: 27.7 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.95 Å
  • R-Value Free: 0.192 
  • R-Value Work: 0.158 
  • R-Value Observed: 0.160 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 45α = 90
b = 66.16β = 101.84
c = 54.98γ = 90
Software Package:
Software NamePurpose
Aimlessdata scaling
REFMACrefinement
PDB_EXTRACTdata extraction

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2017-10-25
    Type: Initial release
  • Version 1.1: 2017-11-22
    Changes: Database references
  • Version 1.2: 2024-01-17
    Changes: Data collection, Database references, Refinement description