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Ramirez UD , Myachina F , Stith L , Jaffe EK
Docking to large allosteric binding sites on protein surfaces
Adv Exp Med Biol. 2010 ;680 :481-8
PMID: 20865533 PMCID: PMC2946403
AbstractThe inactive porphobilinogen synthase (PBGS) hexamer has an oligomer-specific and phylogenetically variable surface cavity that is not present in the active octamer. The octamer and hexamer are components of a dynamic quaternary structure equilibrium characteristic of morpheeins. Small molecules that bind to the hexamer-specific surface cavity, which is at the interface of three subunits, are predicted to act as allosteric inhibitors that function by drawing the oligomeric equilibrium toward the hexamer. We used GLIDE as a tool to enrich a 250,000 molecule library for molecules with enhanced probability of acting as hexamer-stabilizing allosteric inhibitors of PBGS from Yersinia enterocolitica. Eighty-six compounds were tested in vitro and five showed hexamer stabilization. We discuss the application of computational docking to surface cavities as an approach to find allosteric modulators of protein function with specific reference to morpheeins that function as an equilibrium of non-additive quaternary structure assemblies.
NotesRamirez, Ursula D Myachina, Faina Stith, Linda Jaffe, Eileen K P30 CA006927/CA/NCI NIH HHS/United States P30 CA006927-41/CA/NCI NIH HHS/United States R01 ES003654/ES/NIEHS NIH HHS/United States R01 ES003654-24/ES/NIEHS NIH HHS/United States R21 AI 063324/AI/NIAID NIH HHS/United States R21 AI063324-02/AI/NIAID NIH HHS/United States T32 CA009035/CA/NCI NIH HHS/United States T32 CA009035-34/CA/NCI NIH HHS/United States Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't United States Advances in experimental medicine and biology Adv Exp Med Biol. 2010;680:481-8.