Mechanism of allosteric inhibition of RUVBL1-RUVBL2 ATPase by the small molecule CB-6644

• DOI: 10.1016/j.xcrp.2024.101982
• Publication Date: 2024-05-13T14:36:32Z
• Authors: Carmen García-Martín; Andrés López-Perrote; Jasminka Boskovic; Oscar Llorca

The RuvB-like protein 1/2 complex (RUVBL1/2) is a hetero-hexameric ATPase essential in several cellular processes, including chromatin remodeling and the assembly of mechanistic target rapamycin 1 (mTORC1) mTORC2. aminopyrazolone CB-6644, small molecule that allosterically inhibits RUVBL1/2, displays antitumor activity animal models. However, its binding site mechanism action are not yet understood. Here, we applied cryoelectron microscopy (cryo-EM) to determine ∼2.4 Å resolution structure RUVBL1/2 bound ATP which, together with additional biochemical cryo-EM experiments, reveals induces large conformational changes CB-6644 recognizes by interacting at interface between two subunits. traps this ATP-bound conformation prevents hydrolysis. Interestingly, our results suggest couples nucleotide state, domain II (DII), interaction other proteins. Our findings reveal how regulates affected binding.