Neutron diffraction of acetazolamide-bound human carbonic anhydrase II reveals atomic details of drug binding

S. Zoë Fisher, Mayank Aggarwal, Andrey Y. Kovalevsky, David N. Silverman, Robert McKenna

Research output: Contribution to journalArticlepeer-review

88 Scopus citations

Abstract

Carbonic anhydrases (CAs) catalyze the hydration of CO2 forming HCO3- 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.

Original languageEnglish
Pages (from-to)14726-14729
Number of pages4
JournalJournal of the American Chemical Society
Volume134
Issue number36
DOIs
StatePublished - Sep 12 2012
Externally publishedYes

Funding

FundersFunder number
National Institute of General Medical SciencesR01GM071939

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