NIBR
POSTDOCTORAL PROGRAM

WilhelmWeihofenWilhelm Weihofen, PhD
Center for Proteomic Chemistry
Cambridge, Massachusetts, United States

 

G protein-coupled receptors (GPCRs) convert signals from the outside to the inside of a cell. Since many physiological processes rely on these signal transduction events, GPCRs are drug targets in multiple therapeutic areas. For drug discovery purposes it is invaluable to visualize and understand receptor-ligand interactions. This knowledge allows the interpretation of biophysical and biochemical findings and enables rational drug design. However, until recently, we have been limited in applying many of our structural and biophysical tools to GPCRs due to their requirement of a membrane environment. Now, breakthrough developments in protein engineering and crystallography over the past few years have brought the goal of structure-based drug design on GPCRs within reach. The pace of understanding disease-relevant GPCR structural features responsible for the functional selectivity of a disease is accelerating and this improved knowledge will enable us to design more targeted therapies. Additionally, pure and stable GPCRs will open up new possibilities for biophysical characterization and small molecule screening in direct binding assays, augmenting our structural discoveries.

Our lab incorporates these new techniques to generate pure and stable GPCRs and joins them to our already established and powerful biophysical and structural tools. We employ protein crystallography techniques to determine high-resolution GPCR structures and study receptor and receptor-ligand interactions in direct binding assays - surface plasmon resonance and isothermal chemical denaturation. Collectively, these data enable us to learn about the mechanisms of functional regulation and ligand-binding properties of the GPCR target of interest. In addition to studying GPCR function, pure and stable GPCRs are used to pan Fab and nanobody libraries. Initial hits from these efforts are then characterized to filter out conformation-specific binders, which can be used as crystallization chaperones or as conformational biosensors in live cell imaging applications.

Selected Publications

Structure of a Force-Conveying Cadherin Bond Essential for Inner-Ear Mechanotransduction
Sotomayor MM, Weihofen WA, Gaudet R, Corey DP
Nature 2012; 6: 128-32

Structural Determinants of Cadherin-23 Function in Hearing and Deafness
Sotomayor MM*, Weihofen WA*, Gaudet R, Corey DP
Neuron 2010; 66: 85-100
*equal contribution

Structure of a herpesvirus-encoded cysteine protease reveals a unique class of deubiquitinating enzymes
Schlieker C*, Weihofen WA*, Frijns E, Kattenhorn L, Gaudet R, Ploegh HL.
Molecular Cell 2007; 25: 677-87
*equal contribution

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