6GKD

human NBD1 of CFTR in complex with nanobodies D12 and G3a

Summary for 6GKD

• Entry DOI: 10.2210/pdb6gkd/pdb
• Related PRD ID: PRD_900032
• Descriptor: Cystic fibrosis transmembrane conductance regulator, Nanobody D12, Nanobody G3a, ... (8 entities in total)
• Functional Keywords: cystic fibrosis, cftr, nanobodies, thermal stabilization, conformational dynamics, hydrolase
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 18
• Total formula weight: 354281.29

Authors

Sigoillot, M.,Overtus, M.,Grodecka, M.,Scholl, D.,Garcia-Pino, A.,Laeremans, T.,He, L.,Pardon, E.,Hildebrandt, E.,Urbatsch, I.,Steyaert, J.,Riordan, J.R.,Govaerts, C. (deposition date: 2018-05-18, release date: 2019-06-19, Last modification date: 2020-07-29)

Primary citation

Sigoillot, M.,Overtus, M.,Grodecka, M.,Scholl, D.,Garcia-Pino, A.,Laeremans, T.,He, L.,Pardon, E.,Hildebrandt, E.,Urbatsch, I.,Steyaert, J.,Riordan, J.R.,Govaerts, C.
Domain-interface dynamics of CFTR revealed by stabilizing nanobodies.
Nat Commun, 10:2636-2636, 2019

PubMed Abstract: 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.

PubMed: 31201318
DOI: 10.1038/s41467-019-10714-y

Experimental method

X-RAY DIFFRACTION (2.99 Å)