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NINDSNIMHNICHDNIDCDNEINIDCRNIANIAAANIDANHGRI NCCIHNIDDKNIEHSCCB

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Investigator

Lei Shi, Ph.D.

Computational Chemistry and Molecular Biophysics Unit

Chief, Computational Chemistry and Molecular Biophysics Unit, NIDA
Room 1121
Triad Technology Center
333 Cassell Drive
Baltimore MD 21224
Office: 443-740-2774


lei.shi2@nih.gov

Dr. Lei Shi is a tenure-track Investigator and Chief of the Computational Chemistry and Molecular Biophysics Unit at NIDA.

Post-doctoral Training: Center for Molecular Recognition, Columbia University Medical Center (advisor: Dr. Jonathan A. Javitch); Department of Physiology and Biophysics and Institute for Computational Biomedicine, Weill Cornell Medical College (advisor: Dr. Harel Weinstein)

Ph.D.: Pharmacology, Columbia University Medical Center (advisor: Dr. Jonathan A. Javitch)

B.S.: Biochemistry and Molecular Biology, Beijing University



Membrane proteins (MP) initiate intracellular signaling pathways, control the flow of energy and materials in and out of the cell, and thereby account for more than 30% of the entire proteome and 40% of drug targets. Research interests in the lab are focused on identifying common and specific structural basis of MP functions to advance the mechanistic understanding of key cellular processes, from the disparate yet intertwined perspectives of functional mechanisms and molecular recognition. Using a combined approach of computational and experimental analysis, we are interested in elucidating the atomistic details of allosteric conformational transitions and propagations during signal transduction and transport processes. In particular, we investigate the critical structural and dynamic elements that determine ligand binding specificities, the interactions among MP and their coupled proteins, and the associations of MP with the lipid bilayer. The findings allow us to rationally optimize existing and develop new compounds that shift the conformational equilibrium of MP, which will facilitate functional studies and lead to novel drug discovery.

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  • 1) Yano, H; Bonifazi, A; Xu, M; Guthrie, D A; Schneck, S N; Abramyan, A M; Fant, A D; Hong, W C; Newman, A H; Shi, L (2018)
  • Pharmacological profiling of sigma 1 receptor ligands by novel receptor homomer assays
  • Neuropharmacology, 133 , pp. 264-275, ISSN: 1873-7064 (Electronic) 0028-3908
  • 2) Verma, R K; Abramyan, A M; Michino, M; Free, R B; Sibley, D R; Javitch, J A; Lane, J R; Shi, L (2018)
  • The E2.65A mutation disrupts dynamic binding poses of SB269652 at the dopamine D2 and D3 receptors
  • PLoS Comput Biol, 14 (1), pp. e1005948, ISSN: 1553-7358 (Electronic) 1553-734X
  • 3) The role of transmembrane segment 5 (TM5) in Na2 release and the conformational transition of neurotransmitter:sodium symporters toward the inward-open state. Stolzenberg, S; Li, Z; Quick, M; Malinauskaite, L; Nissen, P; Weinstein, H; Javitch, J A; Shi, L. (2017)
  • The role of transmembrane segment 5 (TM5) in Na2 release and the conformational transition of neurotransmitter:sodium symporters toward the inward-open state
  • J Biol Chem, 292 (18), pp. 7372-7384, ISSN: 1083-351X (Electronic) 0021-9258
  • 4) Michino, M; Boateng, C A; Donthamsetti, P; Yano, H; Bakare, O M; Bonifazi, A; Ellenberger, M P; Keck, T M; Kumar, V; Zhu, C; Verma, R; Deschamps, J R; Javitch, J A; Newman, A H; Shi, L (2017)
  • Toward Understanding the Structural Basis of Partial Agonism at the Dopamine D3 Receptor
  • J Med Chem, 60 (2), pp. 580-593, ISSN: 1520-4804 (Electronic) 0022-262
  • 5) Abramyan, A M; Stolzenberg, S; Li, Z; Loland, C J; Noe, F; Shi, L (2017)
  • The Isomeric Preference of an Atypical Dopamine Transporter Inhibitor Contributes to Its Selection of the Transporter Conformation
  • ACS Chem Neurosci, 8 (8), pp. 1735-1746, ISSN: 1948-7193 (Electronic) 1948-7193
  • 6) Stolzenberg, S; Michino, M; LeVine, M V; Weinstein, H; Shi, L. (2016)
  • Computational approaches to detect allosteric pathways in transmembrane molecular machines
  • Biochim Biophys Acta, 1858 (7 Pt B), pp. 1652-62, ISSN: 0006-3002 (Print) 0006-3002
  • 7) Li, Z; Lee, A S; Bracher, S; Jung, H; Paz, A; Kumar, J P; Abramson, J; Quick, M; Shi, L (2015)
  • Structural basis for Na(+)-sensitivity in dopamine D2 and D3 receptors
  • J Biol Chem, 290 (1), pp. 127-41, ISSN: 1083-351X (Electronic) 0021-9258
  • 8) Li, Z; Lee, A S; Bracher, S; Jung, H; Paz, A; Kumar, J P; Abramson, J; Quick, M; Shi, L. (2015)
  • Identification of a second substrate-binding site in solute-sodium symporters
  • J Biol Chem, 290 (1), pp. 127-41, , ISSN: 1083-351X (Electronic) 0021-9258
  • 9) Stolzenberg, S; Quick, M; Zhao, C; Gotfryd, K; Khelashvili, G; Gether, U; Loland, C J; Javitch, J A; Noskov, S; Weinstein, H; Shi, L (2015)
  • Mechanism of the Association between Na+ Binding and Conformations at the Intracellular Gate in Neurotransmitter:Sodium Symporters
  • J Biol Chem, 290 (22), pp. 13992–14003, ISSN: 1083-351X (Electronic); 0021-9258, 215
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