4UEU

Tyrosine kinase AS - a common ancestor of Src and Abl

Replaces:  4CDS

Summary for 4UEU

• Entry DOI: 10.2210/pdb4ueu/pdb
• Descriptor: TYROSINE KINASE AS - A COMMON ANCESTOR OF SRC AND ABL, PHOSPHOMETHYLPHOSPHONIC ACID ADENYLATE ESTER (2 entities in total)
• Functional Keywords: transferase, ancestor protein, amppcp, dfg-in
• Biological source: SYNTHETIC CONSTRUCT
• Total number of polymer chains: 1
• Total formula weight: 31761.74

Authors

Kutter, S.,Wilson, C.,Agafonov, R.V.,Hoemberger, M.S.,Zorba, A.,Halpin, J.C.,Theobald, D.L.,Kern, D. (deposition date: 2014-12-18, release date: 2015-02-18, Last modification date: 2023-12-20)

Primary citation

Wilson, C.,Agafonov, R.V.,Hoemberger, M.,Kutter, S.,Zorba, A.,Halpin, J.,Buosi, V.,Otten, R.,Waterman, D.,Theobald, D.L.,Kern, D.
Kinase Dynamics. Using Ancient Protein Kinases to Unravel a Modern Cancer Drug'S Mechanism.
Science, 347:882-, 2015

PubMed 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.

PubMed: 25700521
DOI: 10.1126/SCIENCE.AAA1823

Experimental method

X-RAY DIFFRACTION (2.95 Å)