6gjs | pdb_00006gjs

Human NBD1 of CFTR in complex with nanobodies D12 and T4

spinqualitylabelsall models 6gjs, resolution 1.95Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6gjs is a 3 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: ATP, MG Activity: Channel-conductance-controlling ATPase, with EC number 3.6.3.49 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [Q20BJ8_HUMAN] Epithelial ion channel that plays an important role in the regulation of epithelial ion and water transport and fluid homeostasis. Mediates the transport of chloride ions across the cell membrane. Channel activity is coupled to ATP hydrolysis. The ion channel is also permeable to HCO(3-); selectivity depends on the extracellular chloride concentration. Exerts its function also by modulating the activity of other ion channels and transporters. Contributes to the regulation of the pH and the ion content of the epithelial fluid layer.[RuleBase:RU362037] Publication Abstract from PubMed The leading cause of cystic fibrosis (CF) is the deletion of phenylalanine 508 (F508del) in the first nucleotide-binding domain (NBD1) of the cystic fibrosis transmembrane conductance regulator (CFTR). The mutation affects the thermodynamic stability of the domain and the integrity of the interface between NBD1 and the transmembrane domain leading to its clearance by the quality control system. Here, we develop nanobodies targeting NBD1 of human CFTR and demonstrate their ability to stabilize both isolated NBD1 and full-length protein. Crystal structures of NBD1-nanobody complexes provide an atomic description of the epitopes and reveal the molecular basis for stabilization. Furthermore, our data uncover a conformation of CFTR, involving detachment of NBD1 from the transmembrane domain, which contrast with the compact assembly observed in cryo-EM structures. This unexpected interface rearrangement is likely to have major relevance for CF pathogenesis but also for the normal function of CFTR and other ABC proteins. Domain-interface dynamics of CFTR revealed by stabilizing nanobodies.,Sigoillot M, Overtus M, Grodecka M, Scholl D, Garcia-Pino A, Laeremans T, He L, Pardon E, Hildebrandt E, Urbatsch I, Steyaert J, Riordan JR, Govaerts C Nat Commun. 2019 Jun 14;10(1):2636. doi: 10.1038/s41467-019-10714-y. PMID:31201318 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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