Snapshots and ensembles of BTK and cIAP1 protein degrader ternary complexes

Unifying Catalysis Framework to Dissect Proteasomal Degradation Paradigms

“…In contrast to the notion that stable ternary complexes can enhance degradation efficiency, Pfizer scientists found that increased rigidity and stability may negatively impact BTK degradation mediated by the recruitment of cIAP1. 34 With a suite of biochemical, biophysical, and structural studies, they showed that in solution ensembles can lead to ternary complex conformations with different degradation profiles upon bivalent degrader recruitment, perhaps stemming from rigidification of the degrader linker or intrinsic rigidity of the ternary complex, or a combination of both. 34 In this scenario, visualizing high-stability ternary complexes from an energy landscape perspective can illustrate the steep activation requirement for productive degradation ( Figure 3 a).…”

“… 34 With a suite of biochemical, biophysical, and structural studies, they showed that in solution ensembles can lead to ternary complex conformations with different degradation profiles upon bivalent degrader recruitment, perhaps stemming from rigidification of the degrader linker or intrinsic rigidity of the ternary complex, or a combination of both. 34 In this scenario, visualizing high-stability ternary complexes from an energy landscape perspective can illustrate the steep activation requirement for productive degradation ( Figure 3 a). In line with recognizing unique attributes of a given ternary complex, Donovan et al conducted a tour de force effort to map the degradable kinome and answer fundamental questions regarding kinase tractability and degradability.…”

Proteolysis targeting chimeras (PROTACs) come of age: entering the third decade of targeted protein degradation

“…In the past several years nearly 10 different ternary complex crystal structures have been solved. 28,59,118,119 As witnessed in the BRD4 BD2 -MZ1-VHL ternary complex, unifying characteristics of these structures are de novo PPIs and the collapse of flexible linkers. Therefore, PROTACs have been optimized using these crystal structures by maximizing induced PPIs and developing rigid linkers that fix the PROTAC in a more active conformation.…”

“…Numerous uncooperative or negatively cooperative PROTACs have been biophysically characterized and crystallized. [118][119][120] Interestingly, even in the case where ternary complexes are not positively cooperative, novel PPIs are generated, as exemplified by the recent publication of cIAP-BTK PROTAC ternary complexes. 119 Potent POI ligands and E3REs or inherent linker flexibility may enable these novel PPIs to form despite the negatively cooperative system.…”

“…[118][119][120] Interestingly, even in the case where ternary complexes are not positively cooperative, novel PPIs are generated, as exemplified by the recent publication of cIAP-BTK PROTAC ternary complexes. 119 Potent POI ligands and E3REs or inherent linker flexibility may enable these novel PPIs to form despite the negatively cooperative system. As with positively cooperative systems, negatively cooperative cIAP-BTK ternary complex PPIs drive specificity and flexible, adaptable linker conformations influence degradation profiles, which our lab has also observed for VHL-p38a PROTACs.…”