Halogen bonds involved in binding of halogenated ligands by protein kinases.
Analysis of 664 known structures of protein kinase complexes with halogenated ligands revealed 424 short contacts between a halogen atom and a potential protein X-bond acceptor, the topology and geometry of which were analyzed according to the type of a halogen atom (X = Cl, Br, I) and a putative protein X-bond acceptor. Among 236 identified halogen bonds, the most represented ones are directed to backbone carbonyls of the hinge region and may replace the pattern of ATP-like hydrogen bonds. Some halogen-π interactions with either aromatic residues or peptide bonds, that accompany the interaction with the hinge region, may possibly enhance ligand selectivity. Interestingly, many of these halogen-π interactions are bifurcated. Geometrical preferences identify iodine as the strongest X-bond donor, less so bromine, while virtually no such preferences were observed for chlorine; and a backbone carbonyl as the strongest X-bond acceptor. The presence of a halogen atom in a ligand additionally affects the properties of proximal hydrogen bonds, which according to geometrical parameters get strengthened, when a nitrogen of a halogenated ligand acts as the hydrogen bond donor.
Institute of Biochemistry and Biophysics PAS, Warszawa, Poland.
Jarosław
J
Poznański
Institute of Biochemistry and Biophysics PAS, Warszawa, Poland.
Maria
M
Winiewska
Institute of Biochemistry and Biophysics PAS, Warszawa, Poland; International Institute of Molecular and Cell Biology, Warszawa, Poland.
Honorata
H
Czapinska
Department - Center of Population Health Monitoring and Analysis, National Institute of Public Health - National Institute of Hygiene, Warszawa, Poland.
Anna
A
Poznańska
Institute of Biochemistry and Biophysics PAS, Warszawa, Poland.
David
D
Shugar
D020134:Catalytic Domain; D006219:Halogens / Q000737:chemistry*; D006801:Humans; D006860:Hydrogen Bonding; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D011494:Protein Kinases / Q000737:chemistry*; D011499:Protein Processing, Post-Translational
D006219:Halogens; D008024:Ligands; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases