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Link between allosteric signal transduction and functional dynamics in a multisubunit enzyme: S-adenosylhomocysteine hydrolase

Title
Link between allosteric signal transduction and functional dynamics in a multisubunit enzyme: S-adenosylhomocysteine hydrolase
Authors
Lee Y.Jeong L.S.Choi S.Hyeon C.
Ewha Authors
정낙신최선
SCOPUS Author ID
최선scopus
Issue Date
2011
Journal Title
Journal of the American Chemical Society
ISSN
0002-7863JCR Link
Citation
vol. 133, no. 49, pp. 19807 - 19815
Indexed
SCI; SCIE; SCOPUS WOS scopus
Abstract
S-adenosylhomocysteine hydrolase (SAHH), a cellular enzyme that plays a key role in methylation reactions including those required for maturation of viral mRNA, is an important drug target in the discovery of antiviral agents. While targeting the active site is a straightforward strategy of enzyme inhibition, evidence of allosteric modulation of active site in many enzymes underscores the molecular origin of signal transduction. Information of co-evolving sequences in SAHH family and the key residues for functional dynamics that can be identified using native topology of the enzyme provide glimpses into how the allosteric signaling network, dispersed over the molecular structure, coordinates intra- and intersubunit conformational dynamics. To study the link between the allosteric communication and functional dynamics of SAHHs, we performed Brownian dynamics simulations by building a coarse-grained model based on the holo and ligand-bound structures. The simulations of ligand-induced transition revealed that the signal of intrasubunit closure dynamics is transmitted to form intersubunit contacts, which in turn invoke a precise alignment of active site, followed by the dimer-dimer rotation that compacts the whole tetrameric structure. Further analyses of SAHH dynamics associated with ligand binding provided evidence of both induced fit and population shift mechanisms and also showed that the transition-state ensemble is akin to the ligand-bound state. Besides the formation of enzyme-ligand contacts at the active site, the allosteric couplings from the residues distal to the active site are vital to the enzymatic function. © 2011 American Chemical Society.
DOI
10.1021/ja2066175
Appears in Collections:
약학대학 > 약학과 > Journal papers
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