PDBsum entry 5eqe

Transferase/transferase inhibitor

PDB id: 5eqe

Contents

Protein chains

353 a.a.

Ligands

5R8 ×2

Waters ×115

PDB id:

5eqe

Name:

Transferase/transferase inhibitor

Title:

Crystal structure of choline kinase alpha-1 bound by [4-[(4-methyl-1, 4-diazepan-1-yl)methyl]phenyl]methanamine (compound 11)

Structure:

Choline kinase alpha. Chain: a, b. Fragment: unp residues 75-457. Synonym: ck,chetk-alpha,ethanolamine kinase,ek. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: chka, chk, cki. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

2.40Å R-factor: 0.225 R-free: 0.263

Authors:

T.Zhou,X.Zhu,D.C.Dalgarno

Key ref:

S.G.Zech et al. (2016). Novel Small Molecule Inhibitors of Choline Kinase Identified by Fragment-Based Drug Discovery. J Med Chem, 59, 671-686. PubMed id: 26700752 DOI: 10.1021/acs.jmedchem.5b01552

Date:

12-Nov-15 Release date: 06-Jan-16

Protein chains

P35790  (CHKA_HUMAN) -  Choline kinase alpha from Homo sapiens

Seq: 457 a.a.

Struc: 353 a.a.

Enzyme reactions

• Enzyme class 1: E.C.2.7.1.32 - choline kinase.
• Reaction: choline + ATP = phosphocholine + ADP + H⁺
• Enzyme class 2: E.C.2.7.1.82 - ethanolamine kinase.
• Reaction: ethanolamine + ATP = phosphoethanolamine + 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/acs.jmedchem.5b01552

J Med Chem 59:671-686 (2016)

PubMed id: 26700752

Novel Small Molecule Inhibitors of Choline Kinase Identified by Fragment-Based Drug Discovery.

S.G.Zech, A.Kohlmann, T.Zhou, F.Li, R.M.Squillace, L.E.Parillon, M.T.Greenfield, D.P.Miller, J.Qi, R.M.Thomas, Y.Wang, Y.Xu, J.J.Miret, W.C.Shakespeare, X.Zhu, D.C.Dalgarno.

ABSTRACT

Choline kinase α (ChoKα) is an enzyme involved in the synthesis of phospholipids and thereby plays key roles in regulation of cell proliferation, oncogenic transformation, and human carcinogenesis. Since several inhibitors of ChoKα display antiproliferative activity in both cellular and animal models, this novel oncogene has recently gained interest as a promising small molecule target for cancer therapy. Here we summarize our efforts to further validate ChoKα as an oncogenic target and explore the activity of novel small molecule inhibitors of ChoKα. Starting from weakly binding fragments, we describe a structure based lead discovery approach, which resulted in novel highly potent inhibitors of ChoKα. In cancer cell lines, our lead compounds exhibit a dose-dependent decrease of phosphocholine, inhibition of cell growth, and induction of apoptosis at low micromolar concentrations. The druglike lead series presented here is optimizable for improvements in cellular potency, drug target residence time, and pharmacokinetic parameters. These inhibitors may be utilized not only to further validate ChoKα as antioncogenic target but also as novel chemical matter that may lead to antitumor agents that specifically interfere with cancer cell metabolism.