View source for 7bcs


==ASCT2 in the presence of the inhibitor Lc-BPE (position "down") in the outward-open conformation.==
<StructureSection load='7bcs' size='340' side='right'caption='[[7bcs]], [[Resolution|resolution]] 3.43&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7BCS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7BCS FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3.43&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=TJ5:(2~{S},4~{S})-4-(4-phenylphenyl)carbonyloxypyrrolidine-2-carboxylic+acid'>TJ5</scene></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=7bcs FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7bcs OCA], [https://pdbe.org/7bcs PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7bcs RCSB], [https://www.ebi.ac.uk/pdbsum/7bcs PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7bcs ProSAT]</span></td></tr>
</table>
<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&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7bcs" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Bonomi M]]
[[Category: Garaeva AA]]
[[Category: Garibsingh RA]]
[[Category: Grewer C]]
[[Category: Ndaru E]]
[[Category: Paulino C]]
[[Category: Schlessinger A]]
[[Category: Shi Y]]
[[Category: Slotboom DJ]]
[[Category: Zielewicz L]]