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A Molecular Dynamics Study of Allosteric Transitions in Leishmania mexicana Pyruvate Kinase.

Abstract
A comparative molecular dynamics analysis of the pyruvate kinase from Leishmania mexicana is presented in the absence and presence of the allosteric effector fructose 2,6-bisphosphate. Comparisons of the simulations of the large 240 kDa apo and holo tetramers show that binding of fructose 2,6-bisphosphate cools the enzyme and reduces dynamic movement, particularly of the B-domain. The reduced dynamic movement of the holo form traps the pyruvate kinase tetramer in its enzymatically active state with the B-domain acting as a lid to cover the active site. The simulations are also consistent with a transition of the mobile active-site α6' helix, which would adopt a helical conformation in the active R-state and a less structured coil conformation in the inactive T-state. Analysis of the rigid body motions over the trajectory highlights the concerted anticorrelated rigid body rocking motion of the four protomers, which drives the T to R transition. The transitions predicted by these simulations are largely consistent with the Monod-Wyman-Changeux model for allosteric activation but also suggest that rigidification or cooling of the overall structure upon effector binding plays an additional role in enzyme activation.
AuthorsAnkita Naithani, Paul Taylor, Burak Erman, Malcolm D Walkinshaw
JournalBiophysical journal (Biophys J) Vol. 109 Issue 6 Pg. 1149-56 (Sep 15 2015) ISSN: 1542-0086 [Electronic] United States
PMID26210208 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2015 Biophysical Society. Published by Elsevier Inc. All rights reserved.
Chemical References
  • Fructosediphosphates
  • Protozoan Proteins
  • fructose 2,6-diphosphate
  • Pyruvate Kinase
Topics
  • Allosteric Regulation
  • Fructosediphosphates (metabolism)
  • Leishmania mexicana
  • Molecular Dynamics Simulation
  • Motion
  • Protein Multimerization
  • Protein Structure, Secondary
  • Protozoan Proteins (metabolism)
  • Pyruvate Kinase (metabolism)

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