Iyengar Laboratory

Aislyn Wist, Ph.D.

Postdoctoral Fellow, Department of Pharmacology and Systems Therapeutics
E-mail: aislyn.wist@mssm.edu

Mailing Address

One Gustave L. Levy Place, Box 1215 New York NY 10029

Training and Education

Ph.D. (2005) Princeton University, Princeton, NJ, USA

Research Assistant (1999 – 2001) Nektar Therapeutics (formerly Inhale Therapeutics), San Carlos, CA, USA

B.A. (1999) Rutgers University, New Brunswick, NJ, USA

Research Interests

Small molecule modulators of G-protein/effector interactions

There is considerable structural information that is available about the interfaces between G–protein subunits and their effectors. The crystal structures for many of these proteins have been solved and interfaces have been studied using a variety of approaches. This makes it feasible to identify small molecule modulators of the interactions between G proteins and their effectors. The major goals of my project are 1) to find small molecule modulators (activators/inhibitors) of two effector enzymes regulated by heterotrimeric G protein subunits using high-throughput screening of compound libraries and 2) to better understand the molecular mechanism of signaling between the G–protein subunits and effector enzymes through the analysis of the structural and chemical properties of the small molecule modulators. The effector enzymes to be studied are adenylyl cyclases 2 and 6 (AC2, AC6) and phospholipase Cß 2 (PLC-ß2). The increase in cAMP levels, caused by activation of AC by Gα_s, has important implications in treating cancer, paralysis and other physiological responses. Membrane inositol phospholipid cleavage by PLCß produces the signaling molecules, phosphatidylinositol 1,4,5–trisphosphate and diacylglycerol, which activate protein kinase C (PKC). PKC has been linked to Alzheimer's disease, cancer, diabetes and others. Thus finding isoform selective small molecule modulators of these effectors can aid in the target identification for new therapeutic agents.

NMR of PLC-ß2 and Gß

Previous studies in the Iyengar lab, used peptides modeled after various domains on Gß that stimulate, inhibit or bind PLC–ß2. Using ¹⁵N and ¹³C labeled versions of these peptides, we hope to elucidate the conformations of these peptides while interacting with PLC–ß2 using various NMR techniques. If successful, this study will shed light on the structure function relationship between PLC–ß2 and Gß.

Publications

Sarkar A, Wist A, Iyengar R. Signaling networks in biology. In Wiley Encyclopedia of Chemical Biology. John Wiley & Sons, Inc. 2008.

Wist, AD, Gu L, Riedl SJ, Shi Y, McLendon GL. Structure-activity based study of the Smac-binding pocket within the BIR3 domain of XIAP. Bioorg Med Chem. 2007 Apr 15;15(8):2935-43.

Kipp RA, Case MA, Wist AD, Cresson CM, Carrell M, Griner E, Wiita A, Albiniak PA, Chai J, Shi Y, Semmelhack MF, McLendon GL. Molecular targeting of inhibitor of apoptosis proteins based on small molecule mimics of natural binding partners. Biochemistry. 2002 Jun 11;41(23):7344-9.

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