Abstract
The 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.
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Acknowledgments
The authors acknowledge Susan Slechta for in vivo testing of inhibitors, the Fox Chase Cancer Center High Performance Computing Cluster, and grant support from the National Institutes of Health grants R01 ES003654 (EKJ), R21 AI063324 (EKJ), P30 CA006927 (FCCC), and T32 CA009035 (Institute for Cancer Research, a component of FCCC).
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Ramirez, U.D., Myachina, F., Stith, L., Jaffe, E.K. (2010). Docking to Large Allosteric Binding Sites on Protein Surfaces. In: Arabnia, H. (eds) Advances in Computational Biology. Advances in Experimental Medicine and Biology, vol 680. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-5913-3_54
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DOI: https://doi.org/10.1007/978-1-4419-5913-3_54
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