PDBsum entry 4csv

Transferase

PDB id: 4csv

Contents

Protein chain

244 a.a.

Ligands

STI

Waters ×56

PDB id:

4csv

Name:

Transferase

Title:

Tyrosine kinase as - a common ancestor of src and abl bound to gleevec

Structure:

Src-abl tyrosine kinase ancestor. Chain: a. Fragment: kinase domain. Engineered: yes

Source:

Synthetic construct. Organism_taxid: 32630. Expressed in: escherichia coli. Expression_system_taxid: 469008.

Resolution:

2.05Å R-factor: 0.190 R-free: 0.242

Authors:

S.Kutter,C.Wilson,L.Cruz,R.V.Agafonov,M.S.Hoemberger,A.Zorba,D.Kern

Key ref:

C.Wilson et al. (2015). Kinase dynamics. Using ancient protein kinases to unravel a modern cancer drug's mechanism. Science, 347, 882-886. PubMed id: 25700521 DOI: 10.1126/science.aaa1823

Date:

10-Mar-14 Release date: 04-Mar-15

Protein chain

No UniProt id for this chain

Struc: 244 a.a.

Enzyme reactions

• Enzyme class: E.C.2.7.10.2 - non-specific protein-tyrosine kinase.
• Reaction: L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H⁺

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

Added reference

DOI no: 10.1126/science.aaa1823

Science 347:882-886 (2015)

PubMed id: 25700521

Kinase dynamics. Using ancient protein kinases to unravel a modern cancer drug's mechanism.

C.Wilson, R.V.Agafonov, M.Hoemberger, S.Kutter, A.Zorba, J.Halpin, V.Buosi, R.Otten, D.Waterman, D.L.Theobald, D.Kern.

ABSTRACT

Macromolecular function is rooted in energy landscapes, where sequence determines not a single structure but an ensemble of conformations. Hence, evolution modifies a protein's function by altering its energy landscape. Here, we recreate the evolutionary pathway between two modern human oncogenes, Src and Abl, by reconstructing their common ancestors. Our evolutionary reconstruction combined with x-ray structures of the common ancestor and pre-steady-state kinetics reveals a detailed atomistic mechanism for selectivity of the successful cancer drug Gleevec. Gleevec affinity is gained during the evolutionary trajectory toward Abl and lost toward Src, primarily by shifting an induced-fit equilibrium that is also disrupted in the clinical T315I resistance mutation. This work reveals the mechanism of Gleevec specificity while offering insights into how energy landscapes evolve.