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Link between allosteric signal transduction and functional dynamics in a multisubunit enzyme: S-adenosylhomocysteine hydrolase
- Link between allosteric signal transduction and functional dynamics in a multisubunit enzyme: S-adenosylhomocysteine hydrolase
- Lee Y.; Jeong L.S.; Choi S.; Hyeon C.
- Ewha Authors
- 정낙신; 최선
- SCOPUS Author ID
- Issue Date
- Journal Title
- Journal of the American Chemical Society
- vol. 133, no. 49, pp. 19807 - 19815
- SCI; SCIE; SCOPUS
- 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.
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