Identification of Core Allosteric Sites through Temperature- and Nucleus-Invariant Chemical Shift Covariance

Biophys J. 2022 May 9:S0006-3495(22)00371-X. doi: 10.1016/j.bpj.2022.05.004. Online ahead of print.ABSTRACTAllosteric regulation is essential to control biological function. In addition, allosteric sites offer a promising venue for selective drug targeting. However, accurate mapping of allosteric sites remains challenging since allostery relies on often subtle, yet functionally relevant, structural and dynamical changes. A viable approach proposed to overcome such challenge is the chemical shift covariance analysis (CHESCA). Although CHESCA offers an exhaustive map of allosteric networks, it is critical to define the core allosteric sites to be prioritized in subsequent functional studies or the design of allosteric drugs. Here we propose two new CHESCA-based methodologies, called temperature CHESCA (T-CHESCA) and CLASS-CHESCA, aimed at narrowing down allosteric maps to the core allosteric residues. Both T- and CLASS-CHESCAs rely on the invariance of core inter-residue correlations to changes in the chemical shifts of the active and inactive conformations interconverting in fast exchange. In the T-CHESCA the chemical shifts of such states are modulated through temperature changes, while in the CLASS-CHESCA through variations in the spin-active nuclei involved in pairwise correlations. The T- and CLASS-CHESCAs as well as complete-linkage CHESCA were applied to the cAMP-binding domain of the exchange protein directly activated by cAMP (EPAC), which serves as a prototypical allo...

Source: Biophysical Journal - May 11, 2022 Category: Physics Authors: Hebatallah Mohamed Ubaidullah Baryar Amir Bashiri Rajeevan Selvaratnam Bryan VanSchouwen Giuseppe Melacini Source Type: research