Neutron Structure Of Human Enzyme-Drug Complex

Researchers have used neutron crystallography for the first time to determine the structure of a human enzyme, carbonic anhydrase, bound to a clinical drug, acetazolamide (J. Am. Chem. Soc., DOI: 10.1021/ja3068098). Robert McKenna of the University of Florida and coworkers found that neutron crystallography makes it possible to visualize hydrogens (or deuteriums), hydrogen bonding, and charge states—molecular features that are not visible with conventional X-ray crystallography and are potentially valuable for rational drug design. Neutron crystallography has been around for decades, and its use to structurally analyze two enzyme-ligand complexes has been reported—but in one case the enzyme wasn’t human and in the other the ligand wasn’t a current drug. Carbonic anhydrase expert Claudiu T. Supuran of the University of Florence, in Italy, comments that the study resolves a controversy about the protonation state of carbonic anhydrase-bound acetazolamide, reveals previously unobserved H-bonding interactions that may help explain the agent’s high activity with some forms of the enzyme, and could be “of great help for the drug design of acetazolamide-like compounds.”