7BCS

ASCT2 in the presence of the inhibitor Lc-BPE (position "down") in the outward-open conformation.

7BCS の概要

• エントリーDOI: 10.2210/pdb7bcs/pdb
• 関連するPDBエントリー: 7BCQ
• EMDBエントリー: 12142
• 分子名称: Neutral amino acid transporter B(0), (2~{S},4~{S})-4-(4-phenylphenyl)carbonyloxypyrrolidine-2-carboxylic acid (2 entities in total)
• 機能のキーワード: solute carrier transporter, membrane protein, homology modeling, cancer metabolism, glutamine deprivation, cryo-em
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 170850.70

構造登録者

Garibsingh, R.A.,Ndaru, E.,Garaeva, A.A.,Shi, Y.,Zielewicz, L.,Bonomi, M.,Slotboom, D.J.,Paulino, C.,Grewer, C.,Schlessinger, A. (登録日: 2020-12-21, 公開日: 2021-09-22, 最終更新日: 2024-07-10)

主引用文献

Garibsingh, R.A.,Ndaru, E.,Garaeva, A.A.,Shi, Y.,Zielewicz, L.,Zakrepine, P.,Bonomi, M.,Slotboom, D.J.,Paulino, C.,Grewer, C.,Schlessinger, A.
Rational design of ASCT2 inhibitors using an integrated experimental-computational approach.
Proc.Natl.Acad.Sci.USA, 118:-, 2021

PubMed Abstract: 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.

PubMed: 34507995
DOI: 10.1073/pnas.2104093118

実験手法

ELECTRON MICROSCOPY (3.43 Å)