The Molecular Mechanism of Substrate Engagement and Immunosuppressant Inhibition of Calcineurin
Figure 6
Potential interaction modes of CN substrates/regulators with CN.
(A) The CN-RII peptide complex obtained by MD. Colors as in Figure 2A, C. CN is shown in surface representation and the RII peptide in dark green with the LxVP motif (LDVP) and phospho-Ser95 as green sticks. LDVP is bound to the LxVP binding pocket (light green), and phospho-Ser95 is bound in the CN active site (cyan). (B) Electrostatic interactions between CN and the RII peptide. The CN electrostatic surface has positively and negatively charged areas colored blue and red, respectively. The LxVP motif and residues in RII that participate in polar interactions with CN are shown as green sticks. (C) Features of selected CN substrates and regulators, including substrates tested in this work (NFAT, Crz1, and the RII peptide). PxIxIT and LxVP motifs are highlighted in yellow and green, respectively, with intervening residues in grey. Regions containing S-T residues that are dephosphorylated by CN are pink. (D) Potential modes of interaction of CN with various binding partners. CN is shown in grey, with the active site in cyan, the PxIxIT docking site in yellow, and the LxVP docking site in green. CN binding partners are shown in blue, with PxIxIT and LxVP motifs in purple and phosphorylated regions shown as red circles. The residues between the two CN docking motifs, or between one docking motif and regions dephosphorylated by CN, are represented as coils, as they are predicted to be unstructured in solution. A238L is the CN-A238L crystal structure.