27 research outputs found
Single Diastereomer of a Macrolactam Core Binds Specifically to Myeloid Cell Leukemia 1 (MCL1)
A direct binding screen of 100 000
sp<sup>3</sup>-rich molecules
identified a single diastereomer of a macrolactam core that binds
specifically to myeloid cell leukemia 1 (MCL1). A comprehensive toolbox
of biophysical methods was applied to validate the original hit and
subsequent analogues and also established a binding mode competitive
with NOXA BH3 peptide. X-ray crystallography of ligand bound to MCL1
reveals a remarkable ligand/protein shape complementarity that diverges
from previously disclosed MCL1 inhibitor costructures
A Maltose-Binding Protein Fusion Construct Yields a Robust Crystallography Platform for MCL1
<div><p>Crystallization of a maltose-binding protein MCL1 fusion has yielded a robust crystallography platform that generated the first apo MCL1 crystal structure, as well as five ligand-bound structures. The ability to obtain fragment-bound structures advances structure-based drug design efforts that, despite considerable effort, had previously been intractable by crystallography. In the ligand-independent crystal form we identify inhibitor binding modes not observed in earlier crystallographic systems. This MBP-MCL1 construct dramatically improves the structural understanding of well-validated MCL1 ligands, and will likely catalyze the structure-based optimization of high affinity MCL1 inhibitors.</p></div