Premium
The Active Site of a Prototypical “Rigid” Drug Target is Marked by Extensive Conformational Dynamics
Author(s) -
Singh Himanshu,
Das Chandan K.,
Vasa Suresh K.,
Grohe Kristof,
Schäfer Lars V.,
Linser Rasmus
Publication year - 2020
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.202009348
Subject(s) - drug discovery , dynamics (music) , molecular dynamics , chemistry , protein dynamics , structural biology , protein structure , kinetics , biophysics , computational chemistry , computational biology , biochemistry , biology , physics , quantum mechanics , acoustics
Drug discovery, in particular optimization of candidates using medicinal chemistry, is generally guided by structural biology. However, for optimizing binding kinetics, relevant for efficacy and off‐target effects, information on protein motion is important. Herein, we demonstrate for the prototypical textbook example of an allegedly “rigid protein” that substantial active‐site dynamics have generally remained unrecognized, despite thousands of medicinal‐chemistry studies on this model over decades. Comparing cryogenic X‐ray structures, solid‐state NMR on micro‐crystalline protein at room temperature, and solution NMR structure and dynamics, supported by MD simulations, we show that under physiologically relevant conditions the pocket is in fact shaped by pronounced open/close conformational‐exchange dynamics. The study, which is of general significance for pharmacological research, evinces a generic pitfall in drug discovery routines.