Many proteins in their unbound structures have cryptic sites that are not appropriately sized for drug binding. We consider here 32 proteins from the recently published CryptoSite set with validated cryptic sites, and study whether the sites remain cryptic in all available X-ray structures of the proteins solved without any ligand bound near the sites. It was shown that only few of these proteins have binding pockets that never form without ligand binding. Sites that are cryptic in some structures but spontaneously form in others are also rare. In most proteins the forming of pockets is impacted by mutations or ligand binding at locations far from the cryptic site. Thus, it appears that in almost all proteins the formation of cryptic sites is governed by allostery. In many cases the interactions between sites result in identifiable movement of some domains, loops, or side chains, but allostery and cryptic site opening may also occur without such interactions by affecting the stability or the dynamics of the protein.

Role of allostery in the opening of protein cryptic sites

ACS Fall 2020 Virtual Meeting

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