Type 1 Serine/Threonine Kinase Receptors (STKR1) transduce a wide spectrum of biological signals mediated by TGF-β superfamily members. The STKR1 activity is tightly controlled by their regulatory glycine-serine rich (GS) domain adjacent to the kinase domain and an FKBP12 protein, however, the molecular mechanism remains unclear. Here, using molecular dynamics simulations, free energy calculations, and WAFEX-guided principal analysis, we identified that allosteric disruption of a conserved salt bridge located near the ATP binding site mediates the physiological and pathological activation of STKR1. Enlightened by this molecular mechanism, we developed a robust protein dynamical network analysis method using a current-flow scheme, and a free energy perturbation-based method for reversible covalent inhibitors design. These two new methods will be used in conjunction for designing next-generation reversible covalent allosteric kinase inhibitors.

Allosteric regulation and reversible covalent drug design for serine/threonine kinase

2019 Fall National Meeting

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