Figure 6.

Proposed desensitization mechanism of p97 to its ATP-competitive and allosteric inhibitors. NMS-873 allosterically inhibits p97 activity by blocking cooperative D2 ATP hydrolysis. CB-5083 functions as an ATP-competitive and D2-selective inhibitor. Our data suggest that intra-subunit control of D2 activity through ATP-bound D1 is critical for p97 sensitivity to this molecule (orange arrow). The P472L mutant, identified from CB-5083–resistant cells, is desensitized to both inhibitors. This mechanism involves enhanced cooperative ATP binding and hydrolysis by D2 that alter its intra-subunit control by ATP-bound D1.