Back to Search Start Over

Targeting the Gatekeeper MET146 of C-Jun N-Terminal Kinase 3 Induces a Bivalent Halogen/Chalcogen Bond

Authors :
Felix Michael Büttner
Thilo Stehle
Christoph Schall
Susanne Hennig
Stefan Zahn
Frank M. Boeckler
Adrian Sievers-Engler
Johannes Heidrich
Francesco Ansideri
Marcel Günther
Stefan Laufer
Andreas Lange
Markus O. Zimmermann
Michael Laemmerhofer
Pierre Koch
Source :
Journal of the American Chemical Society. 137(46)
Publication Year :
2015

Abstract

We target the gatekeeper MET146 of c-Jun N-terminal kinase 3 (JNK3) to exemplify the applicability of X···S halogen bonds in molecular design using computational, synthetic, structural and biophysical techniques. In a designed series of aminopyrimidine-based inhibitors, we unexpectedly encounter a plateau of affinity. Compared to their QM-calculated interaction energies, particularly bromine and iodine fail to reach the full potential according to the size of their σ-hole. Instead, mutation of the gatekeeper residue into leucine, alanine, or threonine reveals that the heavier halides can significantly influence selectivity in the human kinome. Thus, we demonstrate that, although the choice of halogen may not always increase affinity, it can still be relevant for inducing selectivity. Determining the crystal structure of the iodine derivative in complex with JNK3 (4X21) reveals an unusual bivalent halogen/chalcogen bond donated by the ligand and the back-pocket residue MET115. Incipient repulsion from the too short halogen bond increases the flexibility of Cε of MET146, whereas the rest of the residue fails to adapt being fixed by the chalcogen bond. This effect can be useful to induce selectivity, as the necessary combination of methionine residues only occurs in 9.3% of human kinases, while methionine is the predominant gatekeeper (39%).

Details

ISSN :
15205126
Volume :
137
Issue :
46
Database :
OpenAIRE
Journal :
Journal of the American Chemical Society
Accession number :
edsair.doi.dedup.....ca6cee4b9ed0bfb06b847cef3af90192