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Instruments / Technical Area	Publication Details	Published	Actions
I03-Macromolecular Crystallography	An embedded lipid in the multidrug transporter LmrP suggests a mechanism for polyspecificity Vincent Debruycker , Andrew Hutchin , Matthieu Masureel , Emel Ficici , Chloé Martens , Pierre Legrand , Richard A. Stein , Hassane S. Mchaourab , José D. Faraldo-gómez , Han Remaut , Cedric Govaerts Nature Structural & Molecular Biology 10 DOI: 10.1038/s41594-020-0464-y Diamond Proposal Number(s): [12718] Show Abstract ▼ Abstract: Multidrug efflux pumps present a challenge to the treatment of bacterial infections, making it vitally important to understand their mechanism of action. Here, we investigate the nature of substrate binding within Lactococcus lactis LmrP, a prototypical multidrug transporter of the major facilitator superfamily. We determined the crystal structure of LmrP in a ligand-bound outward-open state and observed an embedded lipid in the binding cavity of LmrP, an observation supported by native mass spectrometry analyses. Molecular dynamics simulations suggest that the anionic lipid stabilizes the observed ligand-bound structure. Mutants engineered to disrupt binding of the embedded lipid display reduced transport of some, but not all, antibiotic substrates. Our results suggest that a lipid within the binding cavity could provide a malleable hydrophobic component that allows adaptation to the presence of different substrates, helping to explain the broad specificity of this protein and possibly other multidrug transporters.	Jul 2020
I02-Macromolecular Crystallography I04-Macromolecular Crystallography I24-Microfocus Macromolecular Crystallography	Domain-interface dynamics of CFTR revealed by stabilizing nanobodies Maud Sigoillot , Marie Overtus , Magdalena Grodecka , Daniel Scholl , Abel Garcia-pino , Toon Laeremans , Lihua He , Els Pardon , Ellen Hildebrandt , Ina Urbatsch , Jan Steyaert , John R. Riordan , Cedric Govaerts Nature Communications 10, 2636 DOI: 10.1038/s41467-019-10714-y Diamond Proposal Number(s): [12718, 12718] Open Access Show Abstract ▼ 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.	Jun 2019

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