Millisecond dynamics of BTK reveal kinome-wide conformational plasticity within the apo kinase domain.

ABSTRACT: Bruton tyrosine kinase (BTK) is a key enzyme in B-cell development whose improper regulation causes severe immunodeficiency diseases. Design of selective BTK therapeutics would benefit from improved, in-silico structural modeling of the kinase's solution ensemble. However, this remains challenging due to the immense computational cost of sampling events on biological timescales. In this work, we combine multi-millisecond molecular dynamics (MD) simulations with Markov state models (MSMs) to report on the thermodynamics, kinetics, and accessible states of BTK's kinase domain. Our conformational landscape links the active state to several inactive states, connected via a structurally diverse intermediate. Our calculations predict a kinome-wide conformational plasticity, and indicate the pres

SUBMITTER: Sultan MM 

PROVIDER: S-EPMC5688120 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature