7bct
From Proteopedia
(Difference between revisions)
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==ASCT2 in the presence of the inhibitor ERA-21 in the outward-open conformation.== | ==ASCT2 in the presence of the inhibitor ERA-21 in the outward-open conformation.== | ||
| - | <StructureSection load='7bct' size='340' side='right'caption='[[7bct]]' scene=''> | + | <StructureSection load='7bct' size='340' side='right'caption='[[7bct]], [[Resolution|resolution]] 3.37Å' scene=''> |
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7BCT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7BCT FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[7bct]] is a 3 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7BCT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7BCT FirstGlance]. <br> |
| - | </td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7bct FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7bct OCA], [https://pdbe.org/7bct PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7bct RCSB], [https://www.ebi.ac.uk/pdbsum/7bct PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7bct ProSAT]</span></td></tr> | + | </td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[7bcq|7bcq]], [[7bcs|7bcs]]</div></td></tr> |
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7bct FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7bct OCA], [https://pdbe.org/7bct PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7bct RCSB], [https://www.ebi.ac.uk/pdbsum/7bct PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7bct ProSAT]</span></td></tr> | ||
</table> | </table> | ||
| + | == Function == | ||
| + | [[https://www.uniprot.org/uniprot/AAAT_HUMAN AAAT_HUMAN]] Sodium-dependent amino acids transporter that has a broad substrate specificity, with a preference for zwitterionic amino acids. It accepts as substrates all neutral amino acids, including glutamine, asparagine, and branched-chain and aromatic amino acids, and excludes methylated, anionic, and cationic amino acids (PubMed:8702519). Through binding of the fusogenic protein syncytin-1/ERVW-1 may mediate trophoblasts syncytialization, the spontaneous fusion of their plasma membranes, an essential process in placental development (PubMed:10708449, PubMed:23492904).<ref>PMID:10708449</ref> <ref>PMID:23492904</ref> <ref>PMID:8702519</ref> (Microbial infection) Acts as a cell surface receptor for Feline endogenous virus RD114.<ref>PMID:10051606</ref> <ref>PMID:10196349</ref> (Microbial infection) Acts as a cell surface receptor for Baboon M7 endogenous virus.<ref>PMID:10196349</ref> (Microbial infection) Acts as a cell surface receptor for type D simian retroviruses.<ref>PMID:10196349</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | 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. | ||
| + | |||
| + | Rational design of ASCT2 inhibitors using an integrated experimental-computational approach.,Garibsingh RA, Ndaru E, Garaeva AA, Shi Y, Zielewicz L, Zakrepine P, Bonomi M, Slotboom DJ, Paulino C, Grewer C, Schlessinger A Proc Natl Acad Sci U S A. 2021 Sep 14;118(37). pii: 2104093118. doi:, 10.1073/pnas.2104093118. PMID:34507995<ref>PMID:34507995</ref> | ||
| + | |||
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 7bct" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
| - | [[Category: Bonomi M]] | + | [[Category: Bonomi, M]] |
| - | [[Category: Garaeva | + | [[Category: Garaeva, A A]] |
| - | [[Category: Garibsingh | + | [[Category: Garibsingh, R A]] |
| - | [[Category: Grewer C]] | + | [[Category: Grewer, C]] |
| - | [[Category: Ndaru E]] | + | [[Category: Ndaru, E]] |
| - | [[Category: Paulino C]] | + | [[Category: Paulino, C]] |
| - | [[Category: Schlessinger A]] | + | [[Category: Schlessinger, A]] |
| - | [[Category: Shi Y]] | + | [[Category: Shi, Y]] |
| - | [[Category: Slotboom | + | [[Category: Slotboom, D J]] |
| - | [[Category: Zielewicz L]] | + | [[Category: Zielewicz, L]] |
| + | [[Category: Cancer metabolism]] | ||
| + | [[Category: Cryo-em]] | ||
| + | [[Category: Glutamine deprivation]] | ||
| + | [[Category: Homology modeling]] | ||
| + | [[Category: Membrane protein]] | ||
| + | [[Category: Solute carrier transporter]] | ||
Revision as of 08:59, 29 September 2021
ASCT2 in the presence of the inhibitor ERA-21 in the outward-open conformation.
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