Docking to Large Allosteric Binding Sites on Protein Surfaces

  • Ursula D. Ramirez
  • Faina Myachina
  • Linda Stith
  • Eileen K. Jaffe
Conference paper

DOI: 10.1007/978-1-4419-5913-3_54

Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 680)
Cite this paper as:
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

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.

Keywords

Computational docking GLIDE Hexamer PBGS Protein surfaces 

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Ursula D. Ramirez
  • Faina Myachina
  • Linda Stith
  • Eileen K. Jaffe
    • 1
  1. 1.Fox Chase Cancer CenterPhiladelphiaUSA

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