Cellular and Structural Physiology Institute, Nagoya University, Nagoya, Japan.
Graduate School of Pharmaceutical Sciences, Nagoya University, Nagoya, Japan.
Nature. 2018 Apr;556(7700):214-218. doi: 10.1038/s41586-018-0003-8. Epub 2018 Apr 4.
The gastric proton pump-the H, K-ATPase-is a P-type ATPase responsible for acidifying the gastric juice down to pH 1. This corresponds to a million-fold proton gradient across the membrane of the parietal cell, the steepest known cation gradient of any mammalian tissue. The H, K-ATPase is an important target for drugs that treat gastric acid-related diseases. Here we present crystal structures of the H, K-ATPase in complex with two blockers, vonoprazan and SCH28080, in the luminal-open state, at 2.8 Å resolution. The drugs have partially overlapping but clearly distinct binding modes in the middle of a conduit running from the gastric lumen to the cation-binding site. The crystal structures suggest that the tight configuration at the cation-binding site lowers the pK value of Glu820 sufficiently to enable the release of a proton even into the pH 1 environment of the stomach.
胃质子泵 - H+，K+-ATP 酶是一种 P 型 ATP 酶，负责将胃液酸化至 pH 值 1。这对应于壁细胞膜中质子的百万倍梯度，是已知哺乳动物组织中最陡峭的阳离子梯度。H+，K+-ATP 酶是治疗胃酸相关疾病药物的重要靶点。在这里，我们展示了 H+，K+-ATP 酶与两种抑制剂（沃诺拉赞和 SCH28080）在腔打开状态下的晶体结构，分辨率为 2.8Å。这些药物在从中肠腔到阳离子结合位点的导管中部具有部分重叠但明显不同的结合模式。晶体结构表明，阳离子结合位点的紧密构象使 Glu820 的 pK 值降低到足以使质子即使在胃的 pH 值 1 环境中也能释放。
