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Thursday, 27th October, 2011, 11:00 - 12:00
Understanding allosteric effects in receptor and non-receptor kinases
Protein kinases (PK) are one of the largest and most functionally diverse protein families and are involved in most cellular pathways. PK malfunction is related to an important number of human diseases, such as cancer, diabetes and cardiovascular diseases. Thus, PK represent major targets for drug development. Historically, drug discovery programs have been dominated by efforts to develop antagonists that compete for binding with endogenous ligands at orthosteric sites. However, allosteric drugs might offer several therapeutic advantages over traditional orthosteric ligands, including greater safety and/or selectivity. Here, by combining of state-of-the-art computer simulations as well as spectroscopy, chemical and molecular biology approaches we study in great details complex allosteric effects in the pharmaceutically relevant Abl and FGFr kinases. In Abl a shift of the SH2 domain from the C- to the N-terminus of the catalytic domain has been found to be involved in activation [1]. The allosteric mechanism, by which the SH2 domain induces conformational changes at the active site, is still debated. We have used elastic network models, normal mode analysis, molecular dynamics simulation and mutagenesis to gain insight into the interplay between the SH2 domain and the relevant motifs at the catalytic site. We propose a mechanism, by which the SH2 domain influences the dynamics of the crucial residues directly involved in the catalytic process. In FgFr we use free energy calculations, crystallography and NMR approaches to shed light on the mode of action of a novel allosteric inhibitor. [2]
[1] Nagar B, Hantschel O, Seeliger M, Davies JM, Weis WI, Superti-Furga G, Kuriyan J Molecular Cell 2006, 21, 787-798.
[2] F. Bono et al., submitted.
[2] F. Bono et al., submitted.
Speaker: Dr. Francesco Gervasio - Computational Biophysics Groups. CNIO, Madrid
Room Seminar Room “Xipre” 173.06 (PRBB – 1st floor)
