7q6z
From Proteopedia
Structure of Hedgehog acyltransferase (HHAT) in complex with megabody 177 bound to IMP-1575
Structural highlights
DiseaseHHAT_HUMAN Chondrodysplasia-difference of sex development syndrome. The disease is caused by variants affecting the gene represented in this entry. FunctionHHAT_HUMAN Palmitoyl acyltransferase that catalyzes N-terminal palmitoylation of SHH; which is required for SHH signaling (PubMed:18534984, PubMed:24784881, PubMed:31875564). It also catalyzes N-terminal palmitoylation of DHH (PubMed:24784881). Promotes the transfer of palmitoyl-CoA from the cytoplasmic to the luminal side of the endoplasmic reticulum membrane, where SHH palmitoylation occurs (PubMed:31875564). It is an essential factor for proper embryonic development and testicular organogenesis (PubMed:24784881).[1] [2] [3] [4] Publication Abstract from PubMedThe Sonic Hedgehog (SHH) morphogen pathway is fundamental for embryonic development and stem cell maintenance and is implicated in various cancers. A key step in signaling is transfer of a palmitate group to the SHH N terminus, catalyzed by the multi-pass transmembrane enzyme Hedgehog acyltransferase (HHAT). We present the high-resolution cryo-EM structure of HHAT bound to substrate analog palmityl-coenzyme A and a SHH-mimetic megabody, revealing a heme group bound to HHAT that is essential for HHAT function. A structure of HHAT bound to potent small-molecule inhibitor IMP-1575 revealed conformational changes in the active site that occlude substrate binding. Our multidisciplinary analysis provides a detailed view of the mechanism by which HHAT adapts the membrane environment to transfer an acyl chain across the endoplasmic reticulum membrane. This structure of a membrane-bound O-acyltransferase (MBOAT) superfamily member provides a blueprint for other protein-substrate MBOATs and a template for future drug discovery. Structure, mechanism, and inhibition of Hedgehog acyltransferase.,Coupland CE, Andrei SA, Ansell TB, Carrique L, Kumar P, Sefer L, Schwab RA, Byrne EFX, Pardon E, Steyaert J, Magee AI, Lanyon-Hogg T, Sansom MSP, Tate EW, Siebold C Mol Cell. 2021 Dec 16;81(24):5025-5038.e10. doi: 10.1016/j.molcel.2021.11.018. , Epub 2021 Dec 9. PMID:34890564[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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