Rational design of ASCT2 inhibitors using an integrated experimental-computational approach
| Autor: | Massimiliano Bonomi, Cristina Paulino, Christof Grewer, Paul Zakrepine, Rachel Ann A. Garibsingh, Avner Schlessinger, Dirk Jan Slotboom, Elias Ndaru, Laura Zielewicz, Yueyue Shi, Alisa A. Garaeva |
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| Přispěvatelé: | Icahn School of Medicine at Mount Sinai [New York] (MSSM), Binghamton University [SUNY], State University of New York (SUNY), University of Groningen [Groningen], Bioinformatique structurale - Structural Bioinformatics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), This study was supported by a grant from the NIH (R01 GM108911) to A.S. and C.G. and Grant T32 CA078207 to R.-A.A.G., the NSF Grant 1515028 and Grant R15 GM135843-01 awarded to C.G., the NWO TOP Grant 714.018.003 to D.J.S., and the NWO Veni Grant 722.017.001 and NWO Start-Up Grant 740.018.016 to C.P. M.B. would like to acknowledge the INCEPTION project ANR-16-CONV-0005., ANR-16-CONV-0005,INCEPTION,Institut Convergences pour l'étude de l'Emergence des Pathologies au Travers des Individus et des populatiONs(2016), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Enzymology, Electron Microscopy |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Amino Acid Transport System ASC
Glutamine homology modeling Computational biology Binding Competitive Minor Histocompatibility Antigens Structure-Activity Relationship 03 medical and health sciences Computational Chemistry 0302 clinical medicine Protein Domains Amino acid homeostasis Humans membrane protein Homology modeling Binding site [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry Molecular Biology/Biochemistry [q-bio.BM] 030304 developmental biology 0303 health sciences MD simulations Binding Sites Multidisciplinary Chemistry Cryoelectron Microscopy Rational design solute carrier transporter Biological Sciences Ligand (biochemistry) Protein Structure Tertiary 3. Good health Solute carrier family Molecular Docking Simulation Biophysics and Computational Biology Pharmaceutical Preparations Drug Design cryo-EM 030217 neurology & neurosurgery Intracellular Protein Binding |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America Proceedings of the National Academy of Sciences of the United States of America, 2021, 118 (37), pp.e2104093118. ⟨10.1073/pnas.2104093118⟩ Proceedings of the National Academy of Sciences of the United States of America, National Academy of Sciences, 2021, 118 (37), pp.e2104093118. ⟨10.1073/pnas.2104093118⟩ Proceedings of the National Academy of Sciences of the United States of America, 118(37):e2104093118. NATL ACAD SCIENCES |
| ISSN: | 0027-8424 1091-6490 |
| DOI: | 10.1073/pnas.2104093118⟩ |
| Popis: | Significance The glutamine transporter ASCT2 is an emerging therapeutic target for various cancer types. Here, we use an integrated computational and experimental approach to develop unique ASCT2 inhibitors targeting a conformational state useful for rational drug design. We apply computational chemistry tools such as molecular docking and molecular dynamics simulations, in combination with structure determination with cryo-electron microscopy and synthetic chemistry, to design multiple ASCT2 inhibitors. Our results reveal a unique mechanism of stereospecific inhibition of ASCT2 and highlight the utility of combining state-of-the-art computational and experimental approaches in characterizing challenging human membrane protein targets. 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. |
| Databáze: | OpenAIRE |
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