Co-Mentor: Gopi Shanker, PhD
Chemical Biology & Therapeutics
Cambridge, Massachusetts, United States
One of the main research areas of my laboratory is the modulation of ion channel function using structural biology and biochemical approaches. Ion channels are well-recognized as an important therapeutic target for treating a number of different pathophysiologies. However, they remain challenging drug targets because their precise role in complex biological systems is often unknown, and it is difficult to obtain conformationally pure protein for structural elucidation of their interactions with small molecules and/or functional modulators like toxins. Until recently, we have been limited in applying many of our structural and biophysical tools to ion channels due to their requirement of a membrane environment. Now, breakthrough developments in protein engineering and cryo-electron microscopy over the past few years have brought the goal of structure-based drug design of ion channels within reach. The pace of understanding disease-relevant ion channel structural features responsible for a disease is accelerating and this improved knowledge will enable us to design more targeted therapies.
Our lab uses state-of-the-art technologies to generate pure and stable ion channels and joins them to our already established and powerful biophysical and structural tools. We employ cryo-electron microscopy to determine high-resolution ion channel structures and direct binding assays (such as surface plasmon resonance, NMR, ITC and isothermal chemical denaturation) to probe ion channel-ligand interactions. Collectively, this data enables us to learn about the mechanisms of functional regulation and ligand-binding properties of the ion channel target of interest. In addition to studying ion channel function, we pan Fab and nanobody libraries. Initial hits from these efforts are then characterized to filter out conformation-specific binders, which can be used as tool conformational chaperones or as conformational biosensors in live cell imaging applications.
A NMDA-receptor calcium influx assay sensitive to stimulation by glutamate and glycine/D-serine.
Guo H, Camargo LM, Yeboah F, Digan ME, Niu H, Pan Y, Reiling S, Soler-Llavina G, Weihofen WA, Wang HR, Shanker YG, Stams T, Bill A.
Sci Rep. 2017 Sep 14;7(1):11608.
Crystal Structure and Conformational Change Mechanism of a Bacterial Nramp-Family Divalent Metal Transporter.
Bozzi AT, Bane LB, Weihofen WA, Singharoy A, Guillen ER, Ploegh HL, Schulten K, Gaudet R.
Structure. 2016 Dec 6;24(12):2102-2114.
Structure of a force-conveying cadherin bond essential for inner-ear mechanotransduction.
Sotomayor M, Weihofen WA, Gaudet R, Corey DP.
Nature. 2012 Dec 6;492(7427):128-32.
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