PDBsum entry 5ap2

Transferase

PDB id: 5ap2

Contents

Protein chain

256 a.a.

Ligands

PWU

PDB id:

5ap2

Name:

Transferase

Title:

Naturally occurring mutations in the mps1 gene predispose cells to kinase inhibitor drug resistance.

Structure:

Dual specificity protein kinase ttk. Chain: a. Fragment: kinase domain, unp residues 519-808. Synonym: phosphotyrosine picked threonine-protein kinase, pyt, monopolar spindle kinase 1. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 511693. Expression_system_variant: ai

Resolution:

2.80Å R-factor: 0.197 R-free: 0.254

Authors:

M.D.Gurden,I.M.Westwood,A.Faisal,S.Naud,K.J.Cheung,C.Mcandrew,A.Wood, J.Schmitt,K.Boxall,G.Mak,P.Workman,R.Burke,S.Hoelder,J.Blagg, R.L.M.Van Montfort,S.Linardopoulos

Key ref:

M.D.Gurden et al. (2015). Naturally Occurring Mutations in the MPS1 Gene Predispose Cells to Kinase Inhibitor Drug Resistance. Cancer Res, 75, 3340-3354. PubMed id: 26202014 DOI: 10.1158/0008-5472.CAN-14-3272

Date:

14-Sep-15 Release date: 23-Sep-15

Protein chain

P33981  (TTK_HUMAN) -  Dual specificity protein kinase TTK from Homo sapiens

Seq: 857 a.a.

Struc: 256 a.a.*

* PDB and UniProt seqs differ at 3 residue positions (black crosses)

Enzyme reactions

• Enzyme class: 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⁺

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

reference

DOI no: 10.1158/0008-5472.CAN-14-3272

Cancer Res 75:3340-3354 (2015)

PubMed id: 26202014

Naturally Occurring Mutations in the MPS1 Gene Predispose Cells to Kinase Inhibitor Drug Resistance.

M.D.Gurden, I.M.Westwood, A.Faisal, S.Naud, K.M.Cheung, C.McAndrew, A.Wood, J.Schmitt, K.Boxall, G.Mak, P.Workman, R.Burke, S.Hoelder, J.Blagg, R.L.Van Montfort, S.Linardopoulos.

ABSTRACT

Acquired resistance to therapy is perhaps the greatest challenge to effective clinical management of cancer. With several inhibitors of the mitotic checkpoint kinase MPS1 in preclinical development, we sought to investigate how resistance against these inhibitors may arise so that mitigation or bypass strategies could be addressed as early as possible. Toward this end, we modeled acquired resistance to the MPS1 inhibitors AZ3146, NMS-P715, and CCT251455, identifying five point mutations in the kinase domain of MPS1 that confer resistance against multiple inhibitors. Structural studies showed how the MPS1 mutants conferred resistance by causing steric hindrance to inhibitor binding. Notably, we show that these mutations occur in nontreated cancer cell lines and primary tumor specimens, and that they also preexist in normal lymphoblast and breast tissues. In a parallel piece of work, we also show that the EGFR p.T790M mutation, the most common mutation conferring resistance to the EGFR inhibitor gefitinib, also preexists in cancer cells and normal tissue. Our results therefore suggest that mutations conferring resistance to targeted therapy occur naturally in normal and malignant cells and these mutations do not arise as a result of the increased mutagenic plasticity of cancer cells. Cancer Res; 75(16); 3340-54. ©2015 AACR.