Targeting the Gatekeeper MET146 of C-Jun N-Terminal Kinase 3 Induces a Bivalent Halogen/Chalcogen Bond.
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%).
Molecular Design and Pharmaceutical Biophysics, Institute of Pharmaceutical Sciences, Eberhard Karls Universität Tübingen , Auf der Morgenstelle 8, 72076 Tübingen, Germany.|Center for Bioinformatics Tübingen (ZBIT), Eberhard Karls Universität Tübingen , Sand 1, 72076 Tübingen, Germany.
Andreas
A
Lange
Pharmaceutical and Medicinal Chemistry, Institute of Pharmaceutical Sciences, Eberhard Karls Universität Tübingen , Auf der Morgenstelle 8, 72076 Tübingen, Germany.
Marcel
M
Günther
Interfaculty Institute of Biochemistry, Eberhard Karls Universität Tübingen , Hoppe-Seyler-Str. 4, 72076 Tübingen, Germany.
Felix Michael
FM
Büttner
Molecular Design and Pharmaceutical Biophysics, Institute of Pharmaceutical Sciences, Eberhard Karls Universität Tübingen , Auf der Morgenstelle 8, 72076 Tübingen, Germany.|Center for Bioinformatics Tübingen (ZBIT), Eberhard Karls Universität Tübingen , Sand 1, 72076 Tübingen, Germany.
Markus O
MO
Zimmermann
Molecular Design and Pharmaceutical Biophysics, Institute of Pharmaceutical Sciences, Eberhard Karls Universität Tübingen , Auf der Morgenstelle 8, 72076 Tübingen, Germany.|Center for Bioinformatics Tübingen (ZBIT), Eberhard Karls Universität Tübingen , Sand 1, 72076 Tübingen, Germany.
Johannes
J
Heidrich
Molecular Design and Pharmaceutical Biophysics, Institute of Pharmaceutical Sciences, Eberhard Karls Universität Tübingen , Auf der Morgenstelle 8, 72076 Tübingen, Germany.
Susanne
S
Hennig
Institute of Physical Chemistry, Justus-Liebig-Universität Gießen , Heinrich-Buff-Ring 17, 35392 Gießen, Germany.
Stefan
S
Zahn
Interfaculty Institute of Biochemistry, Eberhard Karls Universität Tübingen , Hoppe-Seyler-Str. 4, 72076 Tübingen, Germany.
Christoph
C
Schall
Pharmaceutical (Bio)Analysis, Institute of Pharmaceutical Sciences, Eberhard Karls Universität Tübingen , Auf der Morgenstelle 8, 72076 Tübingen, Germany.
Adrian
A
Sievers-Engler
Pharmaceutical and Medicinal Chemistry, Institute of Pharmaceutical Sciences, Eberhard Karls Universität Tübingen , Auf der Morgenstelle 8, 72076 Tübingen, Germany.
Francesco
F
Ansideri
Pharmaceutical and Medicinal Chemistry, Institute of Pharmaceutical Sciences, Eberhard Karls Universität Tübingen , Auf der Morgenstelle 8, 72076 Tübingen, Germany.
Pierre
P
Koch
Pharmaceutical (Bio)Analysis, Institute of Pharmaceutical Sciences, Eberhard Karls Universität Tübingen , Auf der Morgenstelle 8, 72076 Tübingen, Germany.
Michael
M
Laemmerhofer
Interfaculty Institute of Biochemistry, Eberhard Karls Universität Tübingen , Hoppe-Seyler-Str. 4, 72076 Tübingen, Germany.|Department of Pediatrics, Vanderbilt University School of Medicine , Nashville, Tennessee 37232, United States.
Thilo
T
Stehle
Pharmaceutical and Medicinal Chemistry, Institute of Pharmaceutical Sciences, Eberhard Karls Universität Tübingen , Auf der Morgenstelle 8, 72076 Tübingen, Germany.
Stefan A
SA
Laufer
Molecular Design and Pharmaceutical Biophysics, Institute of Pharmaceutical Sciences, Eberhard Karls Universität Tübingen , Auf der Morgenstelle 8, 72076 Tübingen, Germany.|Center for Bioinformatics Tübingen (ZBIT), Eberhard Karls Universität Tübingen , Sand 1, 72076 Tübingen, Germany.
Frank M
FM
Boeckler
D018011:Chalcogens / Q000737:chemistry*; D018360:Crystallography, X-Ray; D005454:Fluorescence Polarization; D006219:Halogens / Q000737:chemistry*; D008715:Methionine / Q000378:metabolism*; D048057:Mitogen-Activated Protein Kinase 10 / Q000737:chemistry*
D018011:Chalcogens; D006219:Halogens; D008715:Methionine; D048057:Mitogen-Activated Protein Kinase 10