title: Two-dimensional crystal structure of aquaporin-4 bound to the inhibitor acetazolamide.
abstract: Acetazolamide (AZA) reduces the water permeability of aquaporin-4, the predominant water channel in the brain. We determined the structure of aquaporin-4 in the presence of AZA using electron crystallography. Most of the features of the 5-Å density map were consistent with those of the previously determined atomic model. The map showed a protruding density from near the extracellular pore entrance, which most likely represents the bound AZA. Molecular docking simulations supported the location of the protrusion as the likely AZA-binding site. These findings suggest that AZA reduces water conduction by obstructing the pathway at the extracellular entrance without inducing a large conformational change in the protein.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Nagoya University, Nagoya 464-8601, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Kamegawa
authors.affiliation: Cellular and Structural Physiology Institute, Nagoya University, Nagoya 464-8601, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Hiroaki
authors.affiliation: Cellular and Structural Physiology Institute, Nagoya University, Nagoya 464-8601, Japan tani@cespi.nagoya-u.ac.jp yoshi@cespi.nagoya-u.ac.jp.
authors.forename: Kazutoshi
authors.initials: K
authors.lastname: Tani
authors.affiliation: Graduate School of Pharmaceutical Sciences, Nagoya University, Nagoya 464-8601, Japan Cellular and Structural Physiology Institute, Nagoya University, Nagoya 464-8601, Japan tani@cespi.nagoya-u.ac.jp yoshi@cespi.nagoya-u.ac.jp.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Fujiyoshi
mesh_terms: D000086:Acetazolamide / Q000378:metabolism*; D000818:Animals; D051401:Aquaporin 4 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D001665:Binding Sites / Q000502:physiology; D003461:Crystallography / Q000379:methods; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D025941:Protein Interaction Mapping / Q000379:methods*; D017434:Protein Structure, Tertiary; D051381:Rats
chemical_list: D051401:Aquaporin 4; D000086:Acetazolamide
keywords: 2D crystal; electron crystallography; electron microscopy; inhibitor bound structure; water channel