7BCT
ASCT2 in the presence of the inhibitor ERA-21 in the outward-open conformation.
Summary for 7BCT
| Entry DOI | 10.2210/pdb7bct/pdb |
| Related | 7BCQ 7BCS |
| EMDB information | 12142 12143 |
| Descriptor | Neutral amino acid transporter B(0) (1 entity in total) |
| Functional Keywords | solute carrier transporter, membrane protein, homology modeling, cancer metabolism, glutamine deprivation, cryo-em |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 3 |
| Total formula weight | 169916.71 |
| Authors | Garibsingh, R.A.,Ndaru, E.,Garaeva, A.A.,Shi, Y.,Zielewicz, L.,Bonomi, M.,Slotboom, D.J.,Paulino, C.,Grewer, C.,Schlessinger, A. (deposition date: 2020-12-21, release date: 2021-09-22, Last modification date: 2024-07-10) |
| Primary citation | 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 Cited by 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: 34507995DOI: 10.1073/pnas.2104093118 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.37 Å) |
Structure validation
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