The small molecule BI-2852 induces a nonfunctional dimer of KRAS

In Kessler et al. (1), the small molecule BI-2852 is shown to bind—at nanomolar affinity—to KRAS between switch I and II, inhibiting interactions with effectors. Here, we identify an alternative explanation for the inhibitory activity. While investigating the BI-2852 KRAS complex (Protein Data Bank [PDB] code 6GJ8), we noticed, by revealing the molecules in the neighboring unit cell, BI-2852 induces a KRAS dimer with rotational symmetry. This dimer complex consists of four molecules (two of BI-2852 and two of KRAS; Fig. 1 A ). Fig. 1. Dimer of KRAS with BI-2852. ( A ) Cartoon of BI-2852 KRAS dimer. Lig1 (cyan) and Lig2 (magenta) interact with both Ras1 (beige) and Ras2 (orange). ( B ) KRAS (ribbons) and key side chains are shown. ( C ) Zoom-in of the binding site: salt–bridge interactions shown (dashed lines). ( D ) Lid (green) and Basin (purple) are indicated on Ras1. Both Lig1 and Lig2 are shown on Ras1. The indole rings, colored green and purple, engage the Lid and Basin, respectively. ( E ) Absorbance A 280 plotted as a function of elution volume: … [↵][1]1To whom correspondence may be addressed. Email: trent.balius{at}nih.gov. [1]: #xref-corresp-1-1