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TitleMolecular structures of human ACAT2 disclose mechanism for selective inhibition.
Journal, issue, pagesStructure, Vol. 29, Issue 12, Page 1410-11418.e4, Year 2021
Publish dateDec 2, 2021
AuthorsTao Long / Yang Liu / Xiaochun Li /
PubMed AbstractEndoplasmic reticulum-localized acyl-CoA:cholesterol acyltransferases (ACAT), including ACAT1 and ACAT2, convert cholesterol to cholesteryl esters that become incorporated into lipoproteins or stored ...Endoplasmic reticulum-localized acyl-CoA:cholesterol acyltransferases (ACAT), including ACAT1 and ACAT2, convert cholesterol to cholesteryl esters that become incorporated into lipoproteins or stored in cytosolic lipid droplets. Selective inhibition of ACAT2 has been shown to considerably attenuate hypercholesterolemia and atherosclerosis in mice. Here, we report cryogenic electron microscopy structures of human ACAT2 bound to its specific inhibitor pyripyropene A or the general ACAT inhibitor nevanimibe. Structural analysis reveals that ACAT2 has a topology in membranes similar to that of ACAT1. A catalytic core with an entry site occupied by a cholesterol molecule and another site for allosteric activation of ACAT2 is observed in these structures. Enzymatic assays show that mutations within sites of cholesterol entry or allosteric activation attenuate ACAT2 activity in vitro. Together, these results reveal mechanisms for ACAT2-mediated esterification of cholesterol, providing a blueprint to design new ACAT2 inhibitors for use in the prevention of cardiovascular disease.
External linksStructure / PubMed:34520735 / PubMed Central
MethodsEM (single particle)
Resolution3.87 - 3.93 Å
Structure data

24208

7n6q

EMDB-24208, PDB-7n6q:
Structure of PPPA bound human ACAT2
Method: EM (single particle) / Resolution: 3.87 Å

24209

7n6r

EMDB-24209, PDB-7n6r:
Structure of nevanimibe bound human ACAT2
Method: EM (single particle) / Resolution: 3.93 Å

Chemicals

ChemComp-7T8:
(3S,4R,4aR,6S,6aS,12R,12aS,12bS)-4-[(acetyloxy)methyl]-12-hydroxy-4,6a,12b-trimethyl-11-oxo-9-(pyridin-3-yl)-1,3,4,4a,5,6,6a,12,12a,12b-decahydro-2H,11H-naphtho[2,1-b]pyrano[3,4-e]pyran-3,6-diyl diacetate

ChemComp-CLR:
CHOLESTEROL / Cholesterol

ChemComp-OLA:
OLEIC ACID / Oleic acid

ChemComp-ROV:
nevanimibe

Source
  • homo sapiens (human)
KeywordsTransferase/Inhibitor / Inhibitor / MEMBRANE PROTEIN / Transferase-Inhibitor complex

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