- EMDB-12143: ASCT2 in the presence of the inhibitor ERA-21 in the outward-open... -
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Basic information
Entry
Database: EMDB / ID: EMD-12143
Title
ASCT2 in the presence of the inhibitor ERA-21 in the outward-open conformation.
Map data
Cryo-EM map of ASCT2 in the presence of the inhibitor ERA-21 at 3.37 A resolution in the outward-open conformation. Map was sharpened with a b factor of 173 A2
Sample
Complex: ASCT2 in the presence of the inhibitor ERA-21 in the outward-open conformation.
Protein or peptide: Neutral amino acid transporter B(0)
Keywords
Solute carrier transporter / membrane protein / homology modeling / cancer metabolism / glutamine deprivation / cryo-EM
Function / homology
Function and homology information
glutamine secretion / L-glutamine import across plasma membrane / glutamine transport / L-glutamine transmembrane transporter activity / L-serine transmembrane transporter activity / ligand-gated channel activity / neutral amino acid transport / amino acid transmembrane transporter activity / L-aspartate transmembrane transporter activity / Amino acid transport across the plasma membrane ...glutamine secretion / L-glutamine import across plasma membrane / glutamine transport / L-glutamine transmembrane transporter activity / L-serine transmembrane transporter activity / ligand-gated channel activity / neutral amino acid transport / amino acid transmembrane transporter activity / L-aspartate transmembrane transporter activity / Amino acid transport across the plasma membrane / L-aspartate import across plasma membrane / neutral L-amino acid transmembrane transporter activity / symporter activity / antiporter activity / amino acid transport / RHOJ GTPase cycle / RHOQ GTPase cycle / protein homotrimerization / RHOH GTPase cycle / transport across blood-brain barrier / RAC3 GTPase cycle / RAC1 GTPase cycle / erythrocyte differentiation / basal plasma membrane / melanosome / virus receptor activity / signaling receptor activity / extracellular exosome / membrane / metal ion binding / plasma membrane Similarity search - Function
Sodium:dicarboxylate symporter family signature 2. / Sodium:dicarboxylate symporter / Sodium:dicarboxylate symporter, conserved site / Sodium:dicarboxylate symporter superfamily / Sodium:dicarboxylate symporter family / Sodium:dicarboxylate symporter family signature 1. Similarity search - Domain/homology
Netherlands Organisation for Scientific Research (NWO)
722.017.001
Netherlands
Netherlands Organisation for Scientific Research (NWO)
740.018.016
Netherlands
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
R01 GM108911
United States
National Institutes of Health/National Cancer Institute (NIH/NCI)
T32 CA078207
United States
National Science Foundation (NSF, United States)
1515028
United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
R15 GM135843-01
United States
Netherlands Organisation for Scientific Research (NWO)
714.018.003
Netherlands
Citation
Journal: Proc Natl Acad Sci U S A / Year: 2021 Title: Rational design of ASCT2 inhibitors using an integrated experimental-computational approach. Authors: 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 / 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 ...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.
History
Deposition
Dec 21, 2020
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Header (metadata) release
Sep 22, 2021
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Map release
Sep 22, 2021
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Update
Jul 10, 2024
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Current status
Jul 10, 2024
Processing site: PDBe / Status: Released
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Structure visualization
Movie
Surface view with section colored by density value
Download / File: emd_12143.map.gz / Format: CCP4 / Size: 30.5 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotation
Cryo-EM map of ASCT2 in the presence of the inhibitor ERA-21 at 3.37 A resolution in the outward-open conformation. Map was sharpened with a b factor of 173 A2
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