Neutron Diffraction of
Acetazolamide-Bound Human Carbonic Anhydrase II Reveals Atomic
Details of Drug Binding
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Abstract
Carbonic anhydrases (CAs) catalyze the hydration of CO<sub>2</sub> forming HCO<sub>3</sub><sup>–</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 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