title: Halogen bonding at the ATP binding site of protein kinases: preferred geometry and topology of ligand binding.
abstract: Halogenated ligands have been widely developed as potent, and frequently selective, inhibitors of protein kinases (PK). Herein, all structures of protein kinases complexed with a halogenated ligand, identified in the PDB, were analyzed in the context of eventual contribution of halogen bonding to protein-ligand interactions. Global inspection shows that two carbonyl groups of residues located in the hinge region are the most abundant halogen bond acceptors. In contrast to solution data, well-defined water molecules, located at sites conserved across most PK structures, are also involved in halogen bonding. Analysis of cumulative distributions of halogen-acceptor distances shows that structures displaying short contacts involving a halogen atom are overpopulated, contributing together to clearly defined maxima of 2.82, 2.91 and 2.94Å for chlorine, bromine and iodine, respectively. The angular preference of a halogen bond favors ideal topology (180°, 120°) for iodine. For bromine the distribution is much more dispersed, and no such preference was found for chlorine. This article is part of a Special Issue entitled: Inhibitors of Protein Kinases (2012).
authors: Institute of Biochemistry and Biophysics PAS, Pawińskiego 5a, 02-106 Warszawa, Poland. jarek@ibb.waw.pl
authors: Jarosław
authors: J
authors: Poznański
authors: David
authors: D
authors: Shugar
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry / Q000378:metabolism*; D001665:Binding Sites; D030562:Databases, Protein; D006219:Halogens / Q000737:chemistry / Q000378:metabolism*; D007700:Kinetics; D008024:Ligands; D008274:Magnesium / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000378:metabolism*; D011494:Protein Kinases / Q000737:chemistry / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D014867:Water / Q000737:chemistry / Q000378:metabolism
chemical_list: D006219:Halogens; D008024:Ligands; D047428:Protein Kinase Inhibitors; D014867:Water; D000255:Adenosine Triphosphate; D011494:Protein Kinases; D008274:Magnesium