PDBsum entry 4kb8

Transferase/transferase inhibitor

PDB id: 4kb8

Contents

Protein chains

265 a.a.

285 a.a.

Ligands

1QN ×2

SO4 ×8

1QO ×2

Waters ×254

PDB id:

4kb8

Name:

Transferase/transferase inhibitor

Title:

Ck1d in complex with 1-{4-[3-(4-fluorophenyl)-1-methyl-1h-pyrazol-4- yl]pyridin-2-yl}-n-methylmethanamine ligand

Structure:

Casein kinase i isoform delta. Chain: a, b, c, d. Synonym: cki-delta, ckid, tau-protein kinase csnk1d. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: csnk1d, hckid. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf9

Resolution:

1.95Å R-factor: 0.207 R-free: 0.232

Authors:

S.Liu

Key ref:

S.Mente et al. (2013). Ligand-protein interactions of selective casein kinase 1δ inhibitors. J Med Chem, 56, 6819-6828. PubMed id: 23919824 DOI: 10.1021/jm4006324

Date:

23-Apr-13 Release date: 18-Sep-13

Protein chain

P48730  (KC1D_HUMAN) -  Casein kinase I isoform delta from Homo sapiens

Seq: 415 a.a.

Struc: 265 a.a.

Protein chains

P48730  (KC1D_HUMAN) -  Casein kinase I isoform delta from Homo sapiens

Seq: 415 a.a.

Struc: 285 a.a.

Enzyme reactions

• Enzyme class 1: Chains A, B, C, D: E.C.2.7.11.1 - non-specific serine/threonine protein kinase.
• Reaction:
  1. L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H⁺
  2. L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H⁺
• Enzyme class 2: Chains A, B, C, D: E.C.2.7.11.26 - [tau protein] kinase.
• Reaction:
  1. L-seryl-[tau protein] + ATP = O-phospho-L-seryl-[tau protein] + ADP + H⁺
  2. L-threonyl-[tau protein] + ATP = O-phospho-L-threonyl-[tau protein] + ADP + H⁺

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1021/jm4006324

J Med Chem 56:6819-6828 (2013)

PubMed id: 23919824

Ligand-protein interactions of selective casein kinase 1δ inhibitors.

S.Mente, E.Arnold, T.Butler, S.Chakrapani, R.Chandrasekaran, K.Cherry, K.DiRico, A.Doran, K.Fisher, P.Galatsis, M.Green, M.Hayward, J.Humphrey, J.Knafels, J.Li, S.Liu, M.Marconi, S.McDonald, J.Ohren, V.Paradis, B.Sneed, K.Walton, T.Wager.

ABSTRACT

Casein kinase 1δ (CK1δ) and 1ε (CK1ε) are believed to be necessary enzymes for the regulation of circadian rhythms in all mammals. On the basis of our previously published work demonstrating a CK1ε-preferring compound to be an ineffective circadian clock modulator, we have synthesized a series of pyrazole-substitued pyridine inhibitors, selective for the CK1δ isoform. Additionally, using structure-based drug design, we have been able to exploit differences in the hinge region between CK1δ and p38 to find selective inhibitors that have minimal p38 activity. The SAR, brain exposure, and the effect of these inhibitors on mouse circadian rhythms are described. The in vivo evaluation of these inhibitors demonstrates that selective inhibition of CK1δ at sufficient central exposure levels is capable of modulating circadian rhythms.