Abstract
Obtaining high-throughput structural characterization of small molecule drug candidates bound to their protein target has been hampered by the challenges of cocrystallizing protein-ligand complexes. These challenges include poor ligand solubility, excess ligand molecules disrupting the homogeneity of the sample to be crystallized, and inefficiency in preparing individual complexes and crystal screens for each drug candidate. Crystallizing apo protein followed by soaking with a solution containing the ligand of interest is a powerful tool for rapidly obtaining structural information of ligands. Here, we describe the process of purifying, crystallizing, and soaking PPARγ ligand binding domain as well as strategies for cocrystallizing ligands that are not amenable to soaking.
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