NMR approaches to study proteins integrating globular and disordered domains: the case of c-Src

Nuclear Magnetic Resonance is one of the most versatile structural biology tools. Its unique capacities remain unchallenged by the advances in other techniques, experimental, like cryo-electron microscopy, or computational, such as AlphaFold. In this perspective article we present the role played by various NMR techniques in the study of c-Src, a non-receptor protein tyrosine kinase that contains globular and intrinsically disordered domains. We show (i) how NMR helped chemical biology to discover the regulatory role of the Unique domain, (ii) its role in the characterization of the fuzzy intramolecular complex connecting the disordered region with the globular core through the SH3 domain, (iii) the identification of salt bridges connecting the main post-translational sites of the Unique domain with neighbor basic residues, and, (iv) the characterization of breathing motions and the independent dynamics of the two lobes of the kinase domain.