6IV2

Crystal structure of a bacterial Bestrophin homolog from Klebsiella pneumoniae with a mutation Y211A

6IV2 の概要

• エントリーDOI: 10.2210/pdb6iv2/pdb
• 関連するPDBエントリー: 4wd8
• 分子名称: Bestrophin homolog, ZINC ION (3 entities in total)
• 機能のキーワード: bestrophin-1, homolog, mutation, klebsiella pneumoniae, membrane protein
• 由来する生物種: Klebsiella pneumoniae IS53
• タンパク質・核酸の鎖数: 5
• 化学式量合計: 169045.26

構造登録者

Kittredge, A.,Chen, S.,Yang, T. (登録日: 2018-12-02, 公開日: 2019-11-13, 最終更新日: 2024-05-29)

主引用文献

Ji, C.,Kittredge, A.,Hopiavuori, A.,Ward, N.,Chen, S.,Fukuda, Y.,Zhang, Y.,Yang, T.
Dual Ca2+-dependent gates in human Bestrophin1 underlie disease-causing mechanisms of gain-of-function mutations.
Commun Biol, 2:240-240, 2019

PubMed Abstract: Mutations of human , encoding a Ca-activated Cl channel (hBest1), cause macular degenerative disorders. Best1 homolog structures reveal an evolutionarily conserved channel architecture highlighted by two landmark restrictions (named the "neck" and "aperture", respectively) in the ion conducting pathway, suggesting a unique dual-switch gating mechanism, which, however, has not been characterized well. Using patch clamp and crystallography, we demonstrate that both the neck and aperture in hBest1 are Ca-dependent gates essential for preventing channel leakage resulting from Ca-independent, spontaneous gate opening. Importantly, three patient-derived mutations (D203A, I205T and Y236C) lead to Ca-independent leakage and elevated Ca-dependent anion currents due to enhanced opening of the gates. Moreover, we identify a network of residues critically involved in gate operation. Together, our results suggest an indispensable role of the neck and aperture of hBest1 for channel gating, and uncover disease-causing mechanisms of hBest1 gain-of-function mutations.

PubMed: 31263784
DOI: 10.1038/s42003-019-0433-3

実験手法

X-RAY DIFFRACTION (2.62 Å)