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- W2005366890 abstract "ADAM proteases are implicated in multiple diseases, but no drugs based on ADAM inhibition exist. Most of the ADAM inhibitors developed to date feature zinc-binding moieties that target the active site zinc, which leads to a lack of selectivity and off target toxicity. Targeting secondary substrate binding sites (exosites) can potentially work as an alternative strategy for drug discovery; however, there are only a few reports of potential exosites in ADAM protease structures. In the study presented here, we utilized a series of TNFα-based substrates to probe ADAM10 and 17 interactions with its canonical substrate to identify the structural features that determine ADAM protease substrate specificity. We found that noncatalytic domains of ADAM17 did not directly bind the substrates used in the study but affected the binding nevertheless, most likely because of steric hindrance. Additionally, noncatalytic domains of ADAM17 affected the size/shape of the carbohydrate-binding pocket contained within the catalytic domain of ADAM17. This suggests that noncatalytic domains of ADAM17 play a role in substrate specificity and might help explain differences in substrate repertoires of ADAM17 and its closest homologue, ADAM10. We also addressed the question of which substrate features can affect ADAM protease specificity. We found that all ADAM proteases tested (i.e., ADAM10, 12, and 17) significantly decreased activity when the TNFα-derived sequence was induced into α-helical conformation, suggesting that conformation plays a role in determining ADAM protease substrate specificity. These findings can help in the discovery of ADAM isoform- and substrate-specific inhibitors.Background: Structural determinants of ADAM17 substrate specificity are unknown.Results: ADAM17 activity affected by noncatalytic domains and secondary structure of substrates.Conclusion: Noncatalytic domains and substrate conformation are potentially the key structural elements that determine ADAM17 specificity.Significance: Understanding interaction of ADAM17 with its substrates will assist in discovery ADAM isoform- and substrate-specific inhibitors." @default.
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- W2005366890 date "2004-09-01" @default.
- W2005366890 modified "2023-09-27" @default.
- W2005366890 title "594 Dielectrophoresis (DEP) as sorting technology for microdiagnosis in breast cancer" @default.
- W2005366890 doi "https://doi.org/10.1016/s1359-6349(04)80602-5" @default.
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