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Understanding the conformational changes associated with the binding of small ligands to their biological targets is a fascinating and meaningful question in chemistry, biology and drug discovery. One of the most studied and important is the so-called "DFG-flip" of tyrosine kinases. The conserved three amino-acid DFG motif undergoes an "in to out" movement resulting in a particular inactive conformation to which "type II" kinase inhibitors, such as the anti-cancer drug Imatinib, bind. Despite many studies, the details of this prototypical conformational change are still debated. Here we combine various NMR experiments and surface plasmon resonance with enhanced sampling molecular dynamics simulations to shed light into the conformational dynamics associated with the binding of Imatinib to the proto-oncogene c-Src. We find that both conformational selection and induced fit play a role in the binding mechanism, reconciling opposing views held in the literature. Moreover, an external binding pose and local unfolding (cracking) of the aG helix are observed. We acknowledge the EPSRC, grant [EP/M013898/1] for supporting F.L.G. and G.S., the Comunidad Autonoma de Madrid S2010-BMD-2457 (BIPEDD2) for supporting M.A.M. and R.C.-O.'s Unit, the Ministerio de Educacion and UCL for a PhD fellowship to S.L. PRACE Research Infrastructure resources (SuperMUC, MareNostrum, Curie and Hornet), the e-Infrastructure South (Emerald) and HecBioSim (supported by EPSRC, grant no. EP/L000253/1) for the computational resources. We also acknowledge the MRC Biomedical NMR Center of London for generous NMR time allocation. Access to Research Infrastructures activity in the 7th Framework Programme of the EC (Project number: 261863, Bio-NMR) is acknowledged for financial support to conduct the NMR experiments. Sí

Solution structure of byssal plaque protein Pvfp-5 beta secreted by the Asian green mussel Perna viridis gives molecular insight into mussel adhesion on wet surfaces.Some marine organisms can resist to aqueous tidal environments and adhere tightly on wet surface. This behavior has raised increasing attention for potential applications in medicine, biomaterials, and tissue engineering. In mussels, adhesive forces to the rock are the resultant of proteinic fibrous formations called byssus. We present the solution structure of Pvfp-5 beta, one of the three byssal plaque proteins secreted by the Asian green mussel Perna viridis, and the component responsible for initiating interactions with the substrate. We demonstrate that Pvfp-5 beta has a stably folded structure in agreement with the presence in the sequence of two EGF motifs. The structure is highly rigid except for a few residues affected by slow local motions in the mu s-ms time scale, and differs from the model calculated by artificial intelligence methods for the relative orientation of the EGF modules, which is something where computational methods still underperform. We also show that Pvfp-5 beta is able to coacervate even with no DOPA modification, giving thus insights both for understanding the adhesion mechanism of adhesive mussel proteins, and developing of biomaterials.