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Structure of mouse AsterC (GramD1c) with a novel non-steroidal selective inhibitor
Structural highlights
FunctionASTRC_MOUSE Cholesterol transporter that mediates non-vesicular transport of cholesterol from the plasma membrane (PM) to the endoplasmic reticulum (ER) (PubMed:30220461). Contains unique domains for binding cholesterol and the PM, thereby serving as a molecular bridge for the transfer of cholesterol from the PM to the ER (PubMed:30220461). Plays a crucial role in cholesterol homeostasis and has the unique ability to localize to the PM based on the level of membrane cholesterol (PubMed:30220461). In lipid-poor conditions localizes to the ER membrane and in response to excess cholesterol in the PM is recruited to the endoplasmic reticulum-plasma membrane contact sites (EPCS) which is mediated by the GRAM domain (PubMed:30220461). At the EPCS, the sterol-binding VASt/ASTER domain binds to the cholesterol in the PM and facilitates its transfer from the PM to ER (PubMed:30220461).[1] Publication Abstract from PubMedAster proteins (Aster-A, -B, and -C) are crucial for transporting cholesterol from the plasma membrane (PM) to the endoplasmic reticulum (ER). Asters are expressed in a cell type-specific manner across tissues. Their global disruption leads to varied physiological outcomes given the diverse roles of cholesterol throughout the body. We previously identified sterol analogs, such AI-3d, that inhibit all three Aster proteins. However, their utility is limited by toxicity and off-target effects. Here, we report the development of nonsteroidal Aster inhibitors that are active in cells and in vivo, using binding-guided design to generate compounds with isoform-selective affinities. We found that YKJ-124 is a low-toxicity, Aster-A-preferring inhibitor that elevates PM-accessible cholesterol in primary T cells and potentiates store-operated Ca(2+) entry in Th17 cells, phenocopying Aster-A deficiency. YKJ-300 and YKJ-305 selectively target Aster-C; cocrystal structures and point mutation studies reveal a Ser477-dependent hydrogen bond (Gly in Aster-A/B) that underlies this specificity. We also explored the in vivo consequences of pharmacologic Aster-C inhibition. YKJ-305 treatment of mice blunted fasting-induced hepatic cholesterol transport and cholesterol ester formation, accompanied by compensatory activation of the SREBP2 pathway. Last, we also identify broader-spectrum inhibitors (YKJ-86) and dual Aster-A/C inhibitors (YKJ-262) that drive PM cholesterol accumulation in fibroblasts and human intestinal enteroids. Together, these chemical probes enable isoform-resolved manipulation of Aster-dependent cholesterol trafficking and provide a foundation for developing Aster-targeted therapies for cholesterol dysregulation. Design and structural basis of selective nonsteroidal inhibitors of aster cholesterol trafficking.,Kim H, Romartinez-Alonso B, Xiao X, Gao Y, Kennelly JP, Ferrari A, Li R, Cui L, Whang E, Schwabe JWR, Jung ME, Tontonoz P Proc Natl Acad Sci U S A. 2026 Sep 8;123(36):e2617638123. doi: , 10.1073/pnas.2617638123. Epub 2026 Sep 1. PMID:42679036[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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