8pm6
From Proteopedia
Human bile salt export pump (BSEP) in complex with inhibitor GBM in nanodiscs
Structural highlights
DiseaseABCBB_HUMAN Progressive familial intrahepatic cholestasis type 2;Intrahepatic cholestasis of pregnancy;Benign recurrent intrahepatic cholestasis type 2. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. FunctionABCBB_HUMAN Catalyzes the secretion of conjugated bile salts across the canalicular membrane of hepatocytes in an ATP-dependent manner (PubMed:16332456). Transports taurine-conjugated bile salts more rapidly than glycine-conjugated bile salts (PubMed:16332456).[1] Publication Abstract from PubMedBSEP (ABCB11) is an ATP-binding cassette transporter that is expressed in hepatocytes and extrudes bile salts into the canaliculi of the liver. BSEP dysfunction, caused by mutations or induced by drugs, is frequently associated with severe cholestatic liver disease. We report the cryo-EM structure of glibenclamide-bound human BSEP in nanodiscs, revealing the basis of small-molecule inhibition. Glibenclamide binds the apex of a central binding pocket between the transmembrane domains, preventing BSEP from undergoing conformational changes, and thus rationalizing the reduced uptake of bile salts. We further report two high-resolution structures of BSEP trapped in distinct nucleotide-bound states by using a catalytically inactivated BSEP variant (BSEP(E1244Q)) to visualize a pre-hydrolysis state, and wild-type BSEP trapped by vanadate to visualize a post-hydrolysis state. Our studies provide structural and functional insight into the mechanism of bile salt extrusion and into small-molecule inhibition of BSEP, which may rationalize drug-induced liver toxicity. Structural basis of bile salt extrusion and small-molecule inhibition in human BSEP.,Liu H, Irobalieva RN, Kowal J, Ni D, Nosol K, Bang-Sorensen R, Lancien L, Stahlberg H, Stieger B, Locher KP Nat Commun. 2023 Nov 10;14(1):7296. doi: 10.1038/s41467-023-43109-1. PMID:37949847[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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Categories: Homo sapiens | Large Structures | Bang-Sorensen R | Irobalieva RN | Kowal J | Lancien L | Liu H | Locher KP | Ni D | Nosol K | Stahlberg H | Stieger B
