6ivr | pdb_00006ivr

Crystal structure of a membrane protein W16A

spinqualitylabelsall models 6ivr, resolution 2.80Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6ivr is a 5 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: ACY, CL, EDO, ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed Mutations of human BEST1, encoding a Ca(2+)-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(2+)-dependent gates essential for preventing channel leakage resulting from Ca(2+)-independent, spontaneous gate opening. Importantly, three patient-derived mutations (D203A, I205T and Y236C) lead to Ca(2+)-independent leakage and elevated Ca(2+)-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. Dual Ca(2+)-dependent gates in human Bestrophin1 underlie disease-causing mechanisms of gain-of-function mutations.,Ji C, Kittredge A, Hopiavuori A, Ward N, Chen S, Fukuda Y, Zhang Y, Yang T Commun Biol. 2019 Jun 24;2:240. doi: 10.1038/s42003-019-0433-3. eCollection 2019. PMID:31263784 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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