title: Conformational heterogeneity within the LID domain mediates substrate binding to Escherichia coli adenylate kinase: function follows fluctuations.
abstract: Proteins exist as dynamic ensembles of molecules, implying that protein amino acid sequences evolved to code for both the ground state structure as well as the entire energy landscape of excited states. Accumulating theoretical and experimental evidence suggests that enzymes use such conformational fluctuations to facilitate allosteric processes important for substrate binding and possibly catalysis. This phenomenon can be clearly demonstrated in Escherichia coli adenylate kinase, where experimentally observed local unfolding of the LID subdomain, as opposed to a more commonly postulated rigid-body opening motion, is related to substrate binding. Because "entropy promoting" glycine mutations designed to increase specifically the local unfolding of the LID domain also affect substrate binding, changes in the excited energy landscape effectively tune the function of this enzyme without changing the ground state structure or the catalytic site. Thus, additional thermodynamic information, above and beyond the single folded structure of an enzyme-substrate complex, is likely required for a full and quantitative understanding of how enzymes work.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas Medical Branch at Galveston, 301 University Boulevard, Galveston, TX, 77555-1068, USA, t.parke.schrank@gmail.com.
authors.forename: Travis P
authors.initials: TP
authors.lastname: Schrank
authors.forename: James O
authors.initials: JO
authors.lastname: Wrabl
authors.forename: Vincent J
authors.initials: VJ
authors.lastname: Hilser
mesh_terms: D000263:Adenylate Kinase / Q000737:chemistry* / Q000378:metabolism; D000494:Allosteric Regulation; D004926:Escherichia coli / Q000201:enzymology*; D029968:Escherichia coli Proteins / Q000737:chemistry* / Q000378:metabolism; D005998:Glycine / Q000737:chemistry; D009154:Mutation; D011487:Protein Conformation; D058767:Protein Unfolding; D013379:Substrate Specificity; D013696:Temperature
chemical_list: D029968:Escherichia coli Proteins; D000263:Adenylate Kinase; D005998:Glycine
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