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.
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Authors | Ankita Naithani, Paul Taylor, Burak Erman, Malcolm D Walkinshaw |
Journal | Biophysical journal
(Biophys J)
Vol. 109
Issue 6
Pg. 1149-56
(Sep 15 2015)
ISSN: 1542-0086 [Electronic] United States |
PMID | 26210208
(Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2015 Biophysical Society. Published by Elsevier Inc. All rights reserved. |
Chemical References |
- Fructosediphosphates
- Protozoan Proteins
- fructose 2,6-diphosphate
- Pyruvate Kinase
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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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