Neutron Diffraction of Acetazolamide-Bound Human Carbonic Anhydrase II Reveals Atomic Details of Drug Binding
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- 作者：S. Zo毛 Fisher ; Mayank Aggarwal ; Andrey Y. Kovalevsky ; David N. Silverman ; Robert McKenna
- 刊名：The Journal of the American Chemical Society
- 出版年：2012
- 出版时间：September 12, 2012
- 年：2012
- 卷：134
- 期：36
- 页码：14726-14729
- 全文大小：269K
- 年卷期：v.134,no.36(September 12, 2012)
- ISSN：1520-5126
文摘
Carbonic anhydrases (CAs) catalyze the hydration of CO2 forming HCO3鈥?/sup> 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聽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聽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.