4hul

MATE transporter NorM-NG in complex with Cs+ and monobody

spinqualitylabelsall models 4hul, resolution 3.81Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4hul is a 2 chain structure with sequence from Escherichia coli and Neisseria gonorrhoeae TCDC-NG08107. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: CS Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function M1E1G6_ECOLX Publication Abstract from PubMed Multidrug transporters belonging to the multidrug and toxic compound extrusion (MATE) family expel dissimilar lipophilic and cationic drugs across cell membranes by dissipating a preexisting Na(+) or H(+) gradient. Despite its clinical relevance, the transport mechanism of MATE proteins remains poorly understood, largely owing to a lack of structural information on the substrate-bound transporter. Here we report crystal structures of a Na(+)-coupled MATE transporter NorM from Neisseria gonorrheae in complexes with three distinct translocation substrates (ethidium, rhodamine 6G, and tetraphenylphosphonium), as well as Cs(+) (a Na(+) congener), all captured in extracellular-facing and drug-bound states. The structures revealed a multidrug-binding cavity festooned with four negatively charged amino acids and surprisingly limited hydrophobic moieties, in stark contrast to the general belief that aromatic amino acids play a prominent role in multidrug recognition. Furthermore, we discovered an uncommon cation-pi interaction in the Na(+)-binding site located outside the drug-binding cavity and validated the biological relevance of both the substrate- and cation-binding sites by conducting drug resistance and transport assays. Additionally, we uncovered potential rearrangement of at least two transmembrane helices upon Na(+)-induced drug export. Based on our structural and functional analyses, we suggest that Na(+) triggers multidrug extrusion by inducing protein conformational changes rather than by directly competing for the substrate-binding amino acids. This scenario is distinct from the canonical antiport mechanism, in which both substrate and counterion compete for a shared binding site in the transporter. Collectively, our findings provide an important step toward a detailed and mechanistic understanding of multidrug transport. Structures of a Na+-coupled, substrate-bound MATE multidrug transporter.,Lu M, Symersky J, Radchenko M, Koide A, Guo Y, Nie R, Koide S Proc Natl Acad Sci U S A. 2013 Jan 22. PMID:23341609 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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