6y5v

Structure of Human Potassium Chloride Transporter KCC3b (S45D/T940D/T997D) in KCl

spinqualitylabelsall models 6y5v, resolution 4.08Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 4.08Å Ligands: BMA, NAG Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed Potassium-coupled chloride transporters (KCCs) play crucial roles in regulating cell volume and intracellular chloride concentration. They are characteristically inhibited under isotonic conditions via phospho-regulatory sites located within the cytoplasmic termini. Decreased inhibitory phosphorylation in response to hypotonic cell swelling stimulates transport activity, and dysfunction of this regulatory process has been associated with various human diseases. Here, we present cryo-EM structures of human KCC3b and KCC1, revealing structural determinants for phospho-regulation in both N- and C-termini. We show that phospho-mimetic KCC3b is arrested in an inward-facing state in which intracellular ion access is blocked by extensive contacts with the N-terminus. In another mutant with increased isotonic transport activity, KCC1Delta19, this interdomain interaction is absent, likely due to a unique phospho-regulatory site in the KCC1 N-terminus. Furthermore, we map additional phosphorylation sites as well as a previously unknown ATP/ADP-binding pocket in the large C-terminal domain and show enhanced thermal stabilization of other CCCs by adenine nucleotides. These findings provide fundamentally new insights into the complex regulation of KCCs and may unlock innovative strategies for drug development. Phospho-regulation, nucleotide binding and ion access control in potassium-chloride cotransporters.,Chi G, Ebenhoch R, Man H, Tang H, Tremblay LE, Reggiano G, Qiu X, Bohstedt T, Liko I, Almeida FG, Garneau AP, Wang D, McKinley G, Moreau CP, Bountra KD, Abrusci P, Mukhopadhyay SMM, Fernandez-Cid A, Slimani S, Lavoie JL, Burgess-Brown NA, Tehan B, DiMaio F, Jazayeri A, Isenring P, Robinson CV, Durr KL EMBO J. 2021 May 25:e107294. doi: 10.15252/embj.2020107294. PMID:34031912 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Solute carrier family 12 3D structures Symporter 3D structures

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