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• W4316661605 abstract "Abstract Matrix metalloproteinases (MMPs) regulate the degradation of extracellular matrix (ECM) components in biological processes. MMP activity is controlled by natural tissue inhibitors of metalloproteinases (TIMPs) that non-selectively inhibit the function of multiple MMPs via interaction with the MMPs' Zn 2+ -containing catalytic pocket. Recent studies suggest that TIMPs engineered to confer MMP specificity could be exploited for therapeutic purposes, but obtaining specific TIMP-2 inhibitors has proved to be challenging. Here, in an effort to improve MMP specificity, we incorporated the metal-binding non-canonical amino acids (NCAAs), 3,4-dihydroxyphenylalanine (L-DOPA) and (8-hydroxyquinolin-3-yl)alanine (HqAla), into the MMP-inhibitory N-terminal domain of TIMP2 (N-TIMP2) at selected positions that interact with the catalytic Zn 2+ ion (S2, S69, A70, L100) or with a structural Ca 2+ ion (Y36). Evaluation of the inhibitory potency of the NCAA-containing variants towards MMP-2, MMP-9 and MMP-14 in vitro revealed that most showed a significant loss of inhibitory activity towards MMP-14, but not towards MMP-2 and MMP-9, resulting in increased specificity towards the latter proteases. Substitutions at S69 conferred the best improvement in selectivity for both L-DOPA and HqAla variants. Molecular modeling revealed how MMP-2 and MMP-9 are better able to accommodate the bulky NCAA substituents at the intermolecular interface with N-TIMP2. The models also showed that, rather than coordinating to Zn 2+ , the NCAA side chains formed stabilizing polar interactions at the intermolecular interface with MMP-2 and MMP-9. The findings illustrate how incorporation of NCAAs can be used to probe and exploit differential tolerance for substitution within closely related protein-protein complexes to achieve improved specificity." @default.
• W4316661605 created "2023-01-17" @default.
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• W4316661605 date "2023-01-16" @default.
• W4316661605 modified "2023-10-18" @default.
• W4316661605 title "Utilizing genetic code expansion to modify N-TIMP2 specificity towards MMP-2, MMP-9, and MMP-14" @default.
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• W4316661605 doi "https://doi.org/10.21203/rs.3.rs-2446107/v1" @default.
• W4316661605 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/36712032" @default.
• W4316661605 hasPublicationYear "2023" @default.
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