30JR

Structure of mouse AsterC (GramD1c) with a novel non-steroidal selective inhibitor

This is a non-PDB format compatible entry.

Summary for 30JR

• Entry DOI: 10.2210/pdb30jr/pdb
• Descriptor: Protein Aster-C, 2-[2-[4-(5,6-dimethoxypyridin-3-yl)-2-(trifluoromethyl)phenyl]-4-methyl-1,3-thiazol-5-yl]propan-2-ol, GLYCEROL, ... (6 entities in total)
• Functional Keywords: non-sterol selective inhibitor, aster cholesterol transport protein., lipid transport
• Biological source: Mus musculus (house mouse)
• Total number of polymer chains: 1
• Total formula weight: 21403.78

Authors

Romartinez-Alonso, B.,Kim, H.,Xiao, X.,Tontonoz, P.,Jung, M.,Schwabe, J.W.R. (deposition date: 2026-04-29, release date: 2026-09-09)

Primary citation

Kim, H.,Romartinez-Alonso, B.,Xiao, X.,Gao, Y.,Kennelly, J.P.,Ferrari, A.,Li, R.,Cui, L.,Whang, E.,Schwabe, J.W.R.,Jung, M.E.,Tontonoz, P.
Design and structural basis of selective nonsteroidal inhibitors of aster cholesterol trafficking.
Proc.Natl.Acad.Sci.USA, 123:e2617638123-e2617638123, 2026

PubMed Abstract: Aster 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 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.

PubMed: 42679036
DOI: 10.1073/pnas.2617638123

Experimental method

X-RAY DIFFRACTION (2 Å)