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首页> 外文期刊>Biochemistry >Analysis of the Gastric H,K ATPase for Ion Pathways and Inhibitor Binding Sites
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Analysis of the Gastric H,K ATPase for Ion Pathways and Inhibitor Binding Sites

机译：胃中H，K ATPase的离子途径和抑制剂结合位点分析

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摘要

New models of the gastric H,K ATPase in the E_1K and E_2P states are presented as the first structures of a K+ counter-transport P_2-type ATPase exhibiting ion entry and exit paths. Homology modeling was first used to generate a starting conformation from the srCa ATPase E_2P form (PDB code 1wpg) that contains bound MgADP. Energy minimization of the model showed a conserved adenosine site but nonconserved polyphosphate contacts compared to the srCa ATPase. Molecular dynamics was then employed to expand the luminal entry sufficiently to allow access of the rigid K+ competitive naphthyridine inhibitor, Byk99, to its binding site within the membrane domain. The new E_2P model had increased separation between transmembrane segments M3 through M8, and addition of water in this space showed not only an inhibitor entry path to the luminal vestibule but also a channel leading to the ion binding site. Addition of K+ to the hydrated channel with molecular dynamics modeling of ion movement identified a pathway for K+ from the lumen to the ion binding site to give E_2K. A K+ exit path to the cytoplasm operating during the normal catalytic cycle is also proposed on the basis of an E_1K homology model derived from the E_12Ca~(2+) form of the srCa ATPase (PDB code 1su4). Autodock analyses of the new E_2P model now correctly discriminate between high- and low-affinity K+ competitive inhibitors. Finally, the expanded luminal vestibule of the E_2P model explains high-affinity ouabain binding in a mutant of the H,K ATPase [Qiu et al. (2005) J. Biol. Chem. 280, 32349-32355].
机译：出现在E_1K和E_2P状态的胃H，K ATPase的新模型是K +逆向运输P_2型ATPase的第一个结构，该结构具有离子进入和离开的路径。同源建模首先用于从包含结合的MgADP的srCa ATPase E_2P形式（PDB代码1wpg）生成起始构象。与srCa ATPase相比，模型的能量最小化显示保守的腺苷位点，但不保守的多磷酸盐接触。然后使用分子动力学来充分扩大管腔入口，以允许刚性K +竞争性萘啶抑制剂Byk99进入其在膜结构域内的结合位点。新的E_2P模型增加了跨膜段M3至M8之间的分离，并且在该空间中添加水不仅显示出抑制剂进入腔室前庭的路径，而且还显示了导致离子结合位点的通道。利用离子运动的分子动力学模型将K +添加到水合通道中，确定了K +从内腔到离子结合位点产生E_2K的途径。还基于从srCa ATPase的E_12Ca〜（2+）形式（PDB代码1su4）衍生的E_1K同源性模型，提出了在正常催化循环中向细胞质运行的K +出口路径。现在，对新E_2P模型的自动对接分析可以正确地区分高亲和力和低亲和力K +竞争抑制剂。最后，E_2P模型的扩张腔前庭解释了H，K ATPase突变体中的高亲和哇巴因结合[Qiu等。 （2005）J.Biol。化学280，32349-32355]。

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