Hi Kavya,
I was in a similar situation with a low affinity ligand only soluble in DMSO. Turns out >1% DMSO inhibited binding of the ligand. What I ended up doing was diluting the protein way down in buffer, adding an excess of ligand while keeping the DMSO at <1% of the volume. I allowed the ligand to bind then concentrated the protein-ligand complex back up so the final DMSO concentration was <1% but the protein-ligand complex was much higher. It was the only way I could get crystals.
Good luck!
Lindsey
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