Specific structural features of the various states of ZAP70 kinase domain: (a) The salt bridge D379-R496 and the intermittent hydrogen bonding between N348-S497 (yellow) connect the C- and N-lobes and restrict access to the catalytic cleft.

<p>Additionally these bonds restrict activation loop positioning. (b) The cryptic pocket adjacent to the activation loop spontaneously opened during simulation and was unique to the non-phosphorylated state. Key residues lining the pocket are indicated in gray. Four consensus pharmacophore features were identified by fragment screening. These comprise the acceptor A, donor D, ring R, and a hydrophobic feature H, indicated inset. (c) The cryptic pocket repeatedly opened and closed over the final ~1μs of simulation time, reaching a maximum volume of ~1400 Å ³