title: Neutron diffraction of acetazolamide-bound human carbonic anhydrase II reveals atomic details of drug binding.
abstract: Carbonic anhydrases (CAs) catalyze the hydration of CO(2) forming HCO(3)(-) and a proton, an important reaction for many physiological processes including respiration, fluid secretion, and pH regulation. As such, CA isoforms are prominent clinical targets for treating various diseases. The clinically used acetazolamide (AZM) is a sulfonamide that binds with high affinity to human CA isoform II (HCA II). There are several X-ray structures available of AZM bound to various CA isoforms, but these complexes do not show the charged state of AZM or the hydrogen atom positions of the protein and solvent. Neutron diffraction is a useful technique for directly observing H atoms and the mapping of H-bonding networks that can greatly contribute to rational drug design. To this end, the neutron structure of H/D exchanged HCA II crystals in complex with AZM was determined. The structure reveals the molecular details of AZM binding and the charged state of the bound drug. This represents the first determined neutron structure of a clinically used drug bound to its target.
authors.affiliation: Bioscience Division, Los Alamos National Laboratory, Los Alamos, New Mexico 87545, USA.
authors.forename: S Zoë
authors.initials: SZ
authors.lastname: Fisher
authors.forename: Mayank
authors.initials: M
authors.lastname: Aggarwal
authors.forename: Andrey Y
authors.initials: AY
authors.lastname: Kovalevsky
authors.forename: David N
authors.initials: DN
authors.lastname: Silverman
authors.forename: Robert
authors.initials: R
authors.lastname: McKenna
mesh_terms: D000086:Acetazolamide / Q000737:chemistry*; D001665:Binding Sites; D024402:Carbonic Anhydrase II / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D006859:Hydrogen / Q000737:chemistry*; D006860:Hydrogen Bonding; D008958:Models, Molecular; D015394:Molecular Structure; D033363:Neutron Diffraction; D004364:Pharmaceutical Preparations / Q000737:chemistry*
chemical_list: D004364:Pharmaceutical Preparations; D006859:Hydrogen; D024402:Carbonic Anhydrase II; D000086:Acetazolamide