Menin inhibitors: a 2-in-1 defense versus AML immune evasion

complex, which is consistent with the a2 loop positioning observed in M17prothrombinase.An important consideration here is that M17 harbors 17 strategically engineered mutations that introduce new points of contact enabling it to bind fVa in solution.One could argue that this engineered binding capacity may alter the binding registry of the M17-fVa complex compared to what has been observed in 7TPP.However, the authors argue that this is unlikely, given the extensive binding interface.Furthermore, pseutarin C, which shares only 60% sequence identity with human prothrombinase, forms a structure that is nearly identical to M17prothrombinase complex, suggesting that the overall architecture is preserved in their engineered prothrombinase complex.Another point to consider is that fXa in 7TPP lacks the inserted N-terminus typical of the zymogen form of factor X. Whether that contributes to differences in fVa binding observed between the 2 structures remains unaddressed.Overall, this study aligns with a substantial body of biochemical research and sheds new light on a critical protein-protein interaction with significant modulatory implications for hemostasis.Finally, as we approach atomic resolution for these complexes, increasingly refined structural models are likely to emerge, providing greater insights into key regions that currently remain ambiguous because of limited or poorly resolved density.