PDBsum entry 4mq1

Transferase/transferase inhibitor

PDB id: 4mq1

Contents

Protein chains

346 a.a.

329 a.a.

Ligands

2C3 ×4

1PE ×6

SO4 ×8

Waters ×470

PDB id:

4mq1

Name:

Transferase/transferase inhibitor

Title:

The crystal structure of dyrk1a with a bound pyrido[2,3-d]pyrimidine inhibitor

Structure:

Dual specificity tyrosine-phosphorylation-regulated kinase 1a. Chain: a, b, c, d. Fragment: unp residues 127-485. Synonym: dual specificity yak1-related kinase, hp86, protein kinase minibrain homolog, mnbh, hmnb. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: dyrk1a, dyrk, mnb, mnbh. Expressed in: escherichia coli. Expression_system_taxid: 469008.

Resolution:

2.35Å R-factor: 0.204 R-free: 0.246

Authors:

C.M.Lukacs,C.A.Janson,C.Garvie,L.Liang

Key ref:

K.Anderson et al. (2013). Pyrido[2,3-d]pyrimidines: discovery and preliminary SAR of a novel series of DYRK1B and DYRK1A inhibitors. Bioorg Med Chem Lett, 23, 6610-6615. PubMed id: 24239188 DOI: 10.1016/j.bmcl.2013.10.055

Date:

15-Sep-13 Release date: 11-Dec-13

Protein chains

Q13627  (DYR1A_HUMAN) -  Dual specificity tyrosine-phosphorylation-regulated kinase 1A from Homo sapiens

Seq: 763 a.a.

Struc: 346 a.a.

Protein chain

Q13627  (DYR1A_HUMAN) -  Dual specificity tyrosine-phosphorylation-regulated kinase 1A from Homo sapiens

Seq: 763 a.a.

Struc: 329 a.a.

Enzyme reactions

• Enzyme class 2: Chains A, B, C, D: E.C.2.7.11.23 - [RNA-polymerase]-subunit kinase.
• Reaction: [DNA-directed RNA polymerase] + ATP = phospho-[DNA-directed RNA polymerase] + ADP + H⁺
• Enzyme class 3: Chains A, B, C, D: E.C.2.7.12.1 - dual-specificity 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⁺
  3. L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[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: 10.1016/j.bmcl.2013.10.055

Bioorg Med Chem Lett 23:6610-6615 (2013)

PubMed id: 24239188

Pyrido[2,3-d]pyrimidines: discovery and preliminary SAR of a novel series of DYRK1B and DYRK1A inhibitors.

K.Anderson, Y.Chen, Z.Chen, R.Dominique, K.Glenn, Y.He, C.Janson, K.C.Luk, C.Lukacs, A.Polonskaia, Q.Qiao, A.Railkar, P.Rossman, H.Sun, Q.Xiang, M.Vilenchik, P.Wovkulich, X.Zhang.

ABSTRACT

DYRK1B is a kinase over-expressed in certain cancer cells (including colon, ovarian, pancreatic, etc.). Recent publications have demonstrated inhibition of DYRK1B could be an attractive target for cancer therapy. From a data-mining effort, the team has discovered analogues of pyrido[2,3-d]pyrimidines as potent enantio-selective inhibitors of DYRK1B. Cells treated with a tool compound from this series showed the same cellular effects as down regulation of DYRK1B with siRNA. Such effects are consistent with the proposed mechanism of action. Progress of the SAR study is presented.