Document Type
Article
Language
eng
Format of Original
2 p.
Publication Date
2-24-2010
Publisher
American Chemical Society
Source Publication
Journal of the American Chemical Society
Source ISSN
1520-5126
Original Item ID
DOI: 10.1021/ja906244j
Abstract
Phosphomevalonate kinase (PMK) catalyzes phosphoryl transfer from adenosine triphosphate (ATP) to mevalonate 5-phosphate (M5P) on the pathway for synthesizing cholesterol and other isoprenoids. To permit this reaction, its substrates must be brought proximal, which would result in a significant and repulsive buildup of negative charge. To facilitate this difficult task, PMK contains 17 arginines and eight lysines. However, the way in which this charge neutralization and binding is achieved, from a structural and dynamics perspective, is not known. More broadly, the role of arginine side-chain dynamics in binding of charged substrates has not been experimentally defined for any protein to date. Herein we report a characterization of changes to the dynamical state of the arginine side chains in PMK due to binding of its highly charged substrates, ATP and M5P. These studies were facilitated by the use of arginine-selective labeling to eliminate spectral overlap. Model-free analysis indicated that while substrate binding has little effect on the arginine backbone dynamics, binding of either substrate leads to significant rigidification of the arginine side chains throughout the protein, even those that are >8 Å from the binding site. Such a global rigidification of arginine side chains is unprecedented and suggests that there are long-range electrostatic interactions of sufficient strength to restrict the motion of arginine side chains on the picosecond-to-nanosecond time scale. It will be interesting to see whether such effects are general for arginine residues in proteins that bind highly charged substrates, once additional studies of arginine side-chain dynamics are reported.
Recommended Citation
Olson, Andrew L.; Cai, Sheng; Herdendorf, Timothy J.; Miziorko, Henry M.; and Sem, Daniel S., "NMR Dynamics Investigation of Ligand-Induced Changes of Main and Side-Chain Arginine N-H’s in Human Phosphomevalonate Kinase" (2010). Chemistry Faculty Research and Publications. 409.
https://epublications.marquette.edu/chem_fac/409
Comments
Accepted version. Journal of the American Chemical Society, Vol. 132, No. 7 (February 24, 2010): 2102-2103. DOI. © 2010 American Chemical Society. Used with permission.