biostudies-literatureCimermancic PNCRR NIH HHSHoward Hughes Medical InstituteNIAID NIH HHSNational Institutes of HealthHoward Hughes Predoctoral FellowshipA. P. Giannini Foundation Postdoctoral Research FellowshipNIDDK NIH HHSKrevans FellowshipNCI NIH HHSBayer Science and Education FoundationNIGMS NIH HHSNIH HHSNational Science Foundation709-719https://www.ebi.ac.uk/biostudies/studies/S-EPMC4794384biostudies-literatureUnknown428(4)Many proteins have small-molecule binding pockets that are not easily detectable in the ligand-free structures. These cryptic sites require a conformational change to become apparent; a cryptic site can therefore be defined as a site that forms a pocket in a holo structure, but not in the apo structure. Because many proteins appear to lack druggable pockets, understanding and accurately identifying cryptic sites could expand the set of drug targets. Previously, cryptic sites were identified experimentally by fragment-based ligand discovery and computationally by long molecular dynamics simulations and fragment docking. Here, we begin by constructing a set of structurally defined apo-holo pairs with cryptic sites. Next, we comprehensively characterize the cryptic sites in terms of their seqJournal of molecular biologyCryptoSite: Expanding the Druggable Proteome by Characterization and Prediction of Cryptic Binding Sites.PMC4794384U54 RR022220P30 DK063720U01 GM098256F31 CA180378STC-1231306DP5 OD009180T32 GM008692T32 GM064337R01 GM083960P01 AI091575R21 GM110580U54 GM094662P41 GM109824Keedy DAWoldeyes RAMitchell JCCimermancic PFraser JSSali AWeinkam PRettenmaier TJDemerdash ONBichmann LSchneidman-Duhovny DWells JAfalseCryptoSite: Expanding the Druggable Proteome by Characterization and Prediction of Cryptic Binding Sites.Many proteins have small-molecule binding pockets that are not easily detectable in the ligand-free structures. These cryptic sites require a conformational change to become apparent; a cryptic site can therefore be defined as a site that forms a pocket in a holo structure, but not in the apo structure. Because many proteins appear to lack druggable pockets, understanding and accurately identifying cryptic sites could expand the set of drug targets. Previously, cryptic sites were identified experimentally by fragment-based ligand discovery and computationally by long molecular dynamics simulations and fragment docking. Here, we begin by constructing a set of structurally defined apo-holo pairs with cryptic sites. Next, we comprehensively characterize the cryptic sites in terms of their seq2016-01-01T00:00:00Z2016 Feb2026-04-30T11:20:20.083Z2019-03-27T02:11:16ZS-EPMC47943842685476010.1016/j.jmb.2016.01.029