Crystal structures of the gastric proton pump

Area of Science:

• Biochemistry
• Structural Biology
• Pharmacology

Background:

• The gastric proton pump, H⁺, K⁺-ATPase, generates the steepest known cation gradient in mammals, acidifying gastric juice to pH 1.
• This enzyme is a crucial therapeutic target for managing gastric acid-related disorders.

Purpose of the Study:

• To elucidate the structural mechanisms of H⁺, K⁺-ATPase inhibition by gastric acid blockers.
• To visualize the binding interactions of vonoprazan and SCH28080 with the H⁺, K⁺-ATPase.

Main Methods:

• Determination of crystal structures of the H⁺, K⁺-ATPase in complex with vonoprazan and SCH28080.
• High-resolution X-ray crystallography at 2.8 Å resolution.
• Analysis of drug binding modes within the enzyme's proton conduit.

Main Results:

• Crystal structures were obtained for the H⁺, K⁺-ATPase in a luminal-open state bound to vonoprazan and SCH28080.
• The inhibitors exhibit distinct yet partially overlapping binding orientations within a central conduit leading to the cation-binding site.
• Structural data suggest that a constrained cation-binding site lowers the pK_a of Glu820, facilitating proton release against a steep gradient.

Conclusions:

• The determined structures provide atomic-level insights into the mechanism of H⁺, K⁺-ATPase inhibition.
• Understanding these binding modes can guide the design of more effective drugs targeting gastric acid secretion.
• The findings illuminate the enzyme's ability to release protons into the highly acidic gastric environment.