Discovery of Novel Inhibitors of a Disintegrin and Metalloprotease 17 (ADAM17) Using Glycosylated and Non-glycosylated Substrates

Minond, Dmitriy; Čudić, Mare; Bionda, Nina; Giulianotti, Marc A.; Maida, Laura; Houghten, Richard A.; Fields, Gregg B.

doi:10.1074/jbc.m112.389114

Cited by 52 publications

(75 citation statements)

References 73 publications

(67 reference statements)

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“…1) were previously utilized to study the effects of glycosylation on ADAM protease activity and successfully used as HTS substrates to discover selective exosite-binding inhibitors of ADAM17 (15). In the present study, these substrates were used in combination with free L-galactose to probe the potential carbohydrate-binding site.…”

Section: Resultsmentioning

confidence: 99%

“…Our group recently reported a discovery of a small molecule that inhibits ADAM17 in a non-zinc-binding fashion, which also supports exosite targeting strategies for ADAM17 drug and probe discovery (15).…”

mentioning

confidence: 90%

“…The juxtamembrane region of TNF␣ is disordered according to the Uniprot database entry based on the primary structure composition (P01375, TNFA_ HUMAN), whereas the transmembrane region is predicted to be ␣-helical. We have previously shown that TNF␣-based substrate can form an ␣-helix under conditions emulating the intramembrane environment (15). We were interested to see whether activity of ADAM17 can be modulated by a substrate possessing a distinct secondary structure.…”

Section: Table 2 Effect Of Noncatalytic Domains On Kinetic Parametersmentioning

confidence: 99%

“…4A) (IC 50 ϭ 1.6 Ϯ 0.1, 1.2 Ϯ 0.02, and 0.8 Ϯ 0.02 mM for glycosylated, nonglycosylated, and ␣-helical substrates, respectively). Compound 15, a noncompetitive ADAM17 inhibitor recently reported by our group (15), appreciably inhibited hydrolysis only of the glycosylated substrate (Fig. 4B).…”

mentioning

confidence: 99%

“…We previously reported that substrate glycosylation can differentially affect ADAM activity (15); therefore, it stands to reason that substrate secondary structure can be another, as yet undescribed specificity determinant.…”

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confidence: 99%

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Activity of ADAM17 (a Disintegrin and Metalloprotease 17) Is Regulated by Its Noncatalytic Domains and Secondary Structure of its Substrates

Stawikowska

Čudić

Giulianotti

et al. 2013

Journal of Biological Chemistry

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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 substratespecific inhibitors.

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 90%

Section: Table 2 Effect Of Noncatalytic Domains On Kinetic Parametersmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Activity of ADAM17 (a Disintegrin and Metalloprotease 17) Is Regulated by Its Noncatalytic Domains and Secondary Structure of its Substrates

Stawikowska

Čudić

Giulianotti

et al. 2013

Journal of Biological Chemistry

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Clinical Implications of Compounds Designed to Inhibit ECM‐Modifying Metalloproteinases

2017

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Remodeling of the extracellular matrix (ECM) is crucial in development and homeostasis, but also has a significant role in disease progression. Two metalloproteinase families, the matrix metalloproteinases (MMPs) and a disintegrin and metalloproteases (ADAMs), participate in the remodeling of the ECM, either directly or through the liberation of growth factors and cell surface receptors. The correlation of MMP and ADAM activity to a variety of diseases has instigated numerous drug development programs. However, broad-based and Zn -chelating MMP and ADAM inhibitors have fared poorly in the clinic. Selective MMP and ADAM inhibitors have been described recently based on (a) antibodies or antibody fragments or (b) small molecules designed to take advantage of protease secondary binding sites (exosites) or allosteric sites. Clinical trials have been undertaken with several of these inhibitors, while others are in advanced pre-clinical stages.

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Substrate O‐glycosylation actively regulates extracellular proteolysis

Madzharova,

Sabino,

Kalogeropoulos

et al. 2024

Protein Science

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Extracellular proteolysis critically regulates cellular and tissue responses and is often dysregulated in human diseases. The crosstalk between proteolytic processing and other major post‐translational modifications (PTMs) is emerging as an important regulatory mechanism to modulate protease activity and maintain cellular and tissue homeostasis. Here, we focus on matrix metalloproteinase (MMP)‐mediated cleavages and N‐acetylgalactosamine (GalNAc)‐type of O‐glycosylation, two major PTMs of proteins in the extracellular space. We investigated the influence of truncated O‐glycan trees, also referred to as Tn antigen, following the inactivation of C1GALT1‐specific chaperone 1 (COSMC) on the general and MMP9‐specific proteolytic processing in MDA‐MB‐231 breast cancer cells. Quantitative assessment of the proteome and N‐terminome using terminal amine isotopic labelling of substrates (TAILS) technology revealed enhanced proteolysis by MMP9 within the extracellular proteomes of MDA‐MB‐231 cells expressing Tn antigen. In addition, we detected substantial modifications in the proteome and discovered novel ectodomain shedding events regulated by the truncation of O‐glycans. These results highlight the critical role of mature O‐glycosylation in fine‐tuning proteolytic processing and proteome homeostasis by modulating protein susceptibility to proteolytic degradation. These data suggest a complex interplay between proteolysis and O‐GalNAc glycosylation, possibly affecting cancer phenotypes.

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Discovery of Novel Inhibitors of a Disintegrin and Metalloprotease 17 (ADAM17) Using Glycosylated and Non-glycosylated Substrates

Cited by 52 publications

References 73 publications

Activity of ADAM17 (a Disintegrin and Metalloprotease 17) Is Regulated by Its Noncatalytic Domains and Secondary Structure of its Substrates

Activity of ADAM17 (a Disintegrin and Metalloprotease 17) Is Regulated by Its Noncatalytic Domains and Secondary Structure of its Substrates

Clinical Implications of Compounds Designed to Inhibit ECM‐Modifying Metalloproteinases

Substrate O‐glycosylation actively regulates extracellular proteolysis

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