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-Structure paper
タイトル | Rational design of ASCT2 inhibitors using an integrated experimental-computational approach. |
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ジャーナル・号・ページ | Proc Natl Acad Sci U S A, Vol. 118, Issue 37, Year 2021 |
掲載日 | 2021年9月14日 |
著者 | Rachel-Ann A Garibsingh / Elias Ndaru / Alisa A Garaeva / Yueyue Shi / Laura Zielewicz / Paul Zakrepine / Massimiliano Bonomi / Dirk J Slotboom / Cristina Paulino / Christof Grewer / Avner Schlessinger / |
PubMed 要旨 | ASCT2 (SLC1A5) is a sodium-dependent neutral amino acid transporter that controls amino acid homeostasis in peripheral tissues. In cancer, ASCT2 is up-regulated where it modulates intracellular ...ASCT2 (SLC1A5) is a sodium-dependent neutral amino acid transporter that controls amino acid homeostasis in peripheral tissues. In cancer, ASCT2 is up-regulated where it modulates intracellular glutamine levels, fueling cell proliferation. Nutrient deprivation via ASCT2 inhibition provides a potential strategy for cancer therapy. Here, we rationally designed stereospecific inhibitors exploiting specific subpockets in the substrate binding site using computational modeling and cryo-electron microscopy (cryo-EM). The final structures combined with molecular dynamics simulations reveal multiple pharmacologically relevant conformations in the ASCT2 binding site as well as a previously unknown mechanism of stereospecific inhibition. Furthermore, this integrated analysis guided the design of a series of unique ASCT2 inhibitors. Our results provide a framework for future development of cancer therapeutics targeting nutrient transport via ASCT2, as well as demonstrate the utility of combining computational modeling and cryo-EM for solute carrier ligand discovery. |
リンク | Proc Natl Acad Sci U S A / PubMed:34507995 / PubMed Central |
手法 | EM (単粒子) |
解像度 | 3.37 - 3.43 Å |
構造データ | EMDB-12142: ASCT2 in the presence of the inhibitor Lc-BPE in the outward-open conformation. EMDB-12143, PDB-7bct: |
化合物 | ChemComp-TG2: ChemComp-TJ5: |
由来 |
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キーワード | MEMBRANE PROTEIN (膜タンパク質) / Solute carrier transporter / homology modeling / cancer metabolism / glutamine deprivation / cryo-EM (低温電子顕微鏡法) |