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Structural Biology and Activation Mechanisms of Membrane Receptors

 

 

 Considerable progress has been accomplished in understanding the structure and function of membrane receptors and receptor signaling complexes since the first radioligand binding studies nearly four decades ago. The structures of the extracellular domains of many receptors in diverse classes are now available. However, the structural data have not always provided unambiguous information as to what the relevant physiological structure is, or on the precise nature of the binding and activation mechanism. To get the full picture, it is necessary to integrate structural information, biochemical and molecular biology approaches such as site-directed mutagenesis, photoaffinity crosslinking and bioluminescence resonance energy transfer, kinetics and mathematical modeling. This symposium brings together experts in the various disciplines mentioned above, both seasoned and fresh, for an open-minded debate on how to realize such an integrative approach. A few key systems will be discussed in depth. The prototypical system first discussed will be the ligands of the insulin/insulin-like growth factors and relaxin family, which talk to both receptor tyrosine kinases and G- protein coupled (GPCRs or 7TM) receptors. A strong theme of the meeting is that there are more similarities than previously estimated between the mechanisms of activation of those two classes of receptors including homo- and hetero-dimerization and negative cooperativity, and several key members of those two classes will be analyzed in detail. The study of the biological evolution of the ligand and receptor families and signal transduction mechanisms also provides key information on highly conserved modules. Finally, the promises and challenges in translating our knowledge of the structural biology of membrane receptor signaling to drug discovery will be discussed.