ArticleJournal of molecular modeling2012
Conformational dynamics of threonine 195 and the S1 subsite in functional trypsin variants.
Article in Journal of molecular modeling, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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Who cites it
5 citing papers in PubMed, 6 citations in OpenAlex.
- Dimerization misalignment in human glutamate-oxaloacetate transaminase variants is the primary factor for PLP release.PloS one · 2018Article
- Engineering trypsin for inhibitor resistance.Protein science : a publication of the Protein Society · 2015Article
- Why Ser and not Thr brokers catalysis in the trypsin fold.Biochemistry · 2015Article
- Evaluation of benzoic acid derivatives as sirtuin inhibitors.Bioorganic & medicinal chemistry letters · 2014Article
- Protein dynamics via computational microscope.World journal of methodology · 2012Review
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Replacing the catalytic serine in trypsin with threonine (S195T variant) leads to a nearly complete loss of catalytic activity, which can be partially restored by eliminating the C42-C58 disulfide bond. The 0.69 μs of combined explicit solvent molecular dynamics (MD) simulations revealed continuous rearrangement of T195 with different conformational preferences between five trypsin variants tested. Among three conformational families observed for the T195 residue, one showed the T195 hydroxyl in a conformation analogous to that of the serine residue in wild-type trypsin, positioning the hydroxyl oxygen atom for attack on the carbonyl carbon of the peptide substrate. MD simulations demonstrated that this conformation was more populated for the C42A/C58V/S195T and C42A/C58A/S195T triple variants than for the catalytically inactive S195T variant and correlated with restored enzymatic activities for triple variants. In addition, observation of the increased motion of the S214-G219 segment in the S195T substituted variants suggested an existence of open and closed conformations for the substrate binding pocket. The closed conformation precludes access to the S1 binding site and could further reduce enzymatic activities for triple variants. Double variants with intact serine residues (C42A/C58A/S195 and C42A/C58V/S195) also showed interchange between closed and open conformations for the S214-G219 segment, but to a lesser extent than the triple variants. The increased conformational flexibility of the S1 subsite, which was not observed for the wild-type, correlated with reduced enzymatic activities and suggested a possible mode of substrate regulation for the trypsin variants tested.
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