Fig. 2
From: Cryptic pocket formation underlies allosteric modulator selectivity at muscarinic GPCRs
Cryptic pocket formation allows for binding of the M1-selective PAM BQZ12. a In simulations of the M1 mAChR, Y2.64 was observed to dynamically rotate away from the backbone of C45.50 (top, left) to interact with E7.36 (top, right). This rotation opens a cryptic pocket in the M1 mAChR allosteric binding site. The distance between Y2.64 and C45.50 from two representative simulations of M1 mAChR tracks the dynamic opening and closing of the cryptic pocket (bottom, Supplementary Fig. 2). These simulations were of an active-state receptor with neither orthosteric nor allosteric ligand bound, but inactive-state simulations and simulations with orthosteric ligands yielded similar results (Fig. 3). Snapshots shown at top are from the simulation represented by the light-green trace below. b The allosteric site surface in the initial active-state model of the M1 mAChR is shown in gray. c The opening of the cryptic pocket in simulation substantially alters the shape of the M1 mAChR allosteric site and allows for the docking of BQZ12 by placing the nonplanar arm of BQZ12 into the cryptic pocket. The resulting binding mode agrees with previous mutagenesis data (Supplementary Fig. 4)
