Peptide exosite inhibitors of factor VIIa as anticoagulants

Dennis, Mark S.; Eigenbrot, Charles; Skelton, Nicholas J.; Ultsch, Mark; Santell, Lydia; Dwyer, Mary A.; O'Connell, Mark P.; Lazarus, Robert A.

doi:10.1038/35006574

Cited by 201 publications

(210 citation statements)

References 41 publications

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“…Selective exosite inhibitors of ADAM-related MMP and ADAMTS proteases were discovered by several groups (25)(26)(27)(28)(29)(30), including ours. Exosites are defined as sites outside of the active site that participate in substrate recognition and binding (19). In the case of metalloproteases, an "exosite-binding compound" may simply imply a lack of interaction with the active site zinc (26,28).…”

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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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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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“…The crystal structures of the molecular complex of the active site occupying VIIa, with and without sTF, as well as the crystal structure of zymogen VII, are known (7)(8)(9)(10)(11)(12). The shape of VIIa could be described as a tulip, with the catalytic domain as the flower, the light chain as the stem, and the Gla domain as the bulb.…”

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The 99 and 170 Loop-modified Factor VIIa Mutants Show Enhanced Catalytic Activity without Tissue Factor

Soejima¹,

Yuguchi²,

Mizuguchi³

et al. 2002

Journal of Biological Chemistry

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To elucidate the functions of the surface loops of VIIa, we prepared two mutants, VII-30 and VII-39. The VII-30 mutant had all of the residues in the 99 loop replaced with those of trypsin. In the VII-39 mutant, both the 99 and 170 loops were replaced with those of trypsin. The k cat /K m value for hydrolysis of the chromogenic peptidyl substrate S-2288 by VIIa-30 (103 mM ؊1 s ؊1 ) was 3-fold higher than that of wild-type VIIa (30.3 mM ؊1 s ؊1 ) in the presence of soluble tissue factor (sTF). This enhancement was due to a decrease in the K m value but not to an increase in the k cat value. On the other hand, the k cat /K m value for S-2288 hydrolysis by VIIa-39 (17.9 mM ؊1 s ؊1 ) was 18-fold higher than that of wild-type (1.0 mM ؊1 s ؊1 ) in the absence of sTF, and the value was almost the same as that of wild-type measured in the presence of sTF. This enhancement was due to not only a decrease in the K m value but also to an increase in the k cat value. These results were in good agreement with their susceptibilities to a subsite 1-directed serine protease inhibitor. In our previous paper (Soejima, K., Mizuguchi, J., Yuguchi, M., Nakagaki, T., Higashi, S., and Iwanaga, S. Coagulation factor VIIa (VIIa) 1 is a plasma serine protease that is essential for the initiation of extrinsic blood coagulation (1). When tissue factor (TF) is expressed after injury of the vessel wall, it forms a complex with factor VIIa, and blood coagulation can be initiated. Forming a complex with TF markedly enhances the ability of VIIa to activate factors IX and X. In vitro, the formation of the active complex can be evidenced by measuring the esterolytic and amidolytic activities of VIIa (2, 3); these activities are also enhanced in the presence of soluble TF (sTF) and calcium ions (3-5).Human zymogen VII is a single chain enzyme precursor with an NH 2 -terminal Gla domain, followed by two EGF-like domains, EGF 1 and EGF 2, and a COOH-terminal serine protease domain. , which is composed of a light chain (residues 1-152) with Gla, EGF 1, and EGF 2 domains, and a heavy chain with a serine protease domain (residues 153-406) (6). The crystal structures of the molecular complex of the active site occupying VIIa, with and without sTF, as well as the crystal structure of zymogen VII, are known (7-12). The shape of VIIa could be described as a tulip, with the catalytic domain as the flower, the light chain as the stem, and the Gla domain as the bulb. TF winds around the light chain (the stem) and the Gla domain (the bulb) of FVII.Conversely, the catalytic domain of the coagulation proteases such as VIIa, IXa, Xa, and ␣-thrombin have active sites and internal cores that are similar to those of trypsin. Although these protease domains have a highly homologous three-dimensional structure, they display significant differences in specificity and catalytic activity. Furthermore, each protease requires a specific cofactor to express enhanced catalytic activity and physiological function, which differs from digestive serine proteases such as trypsin a...

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“…Initially, it was employed to identify binders against proteins for the development of therapeutic antibodies 2, 3. Closely related applications are the selection of small‐molecule enzyme inhibitors from phage‐displayed combinatorial peptide libraries4, 5 and the generation of peptide‐dendrimer hybrids targeting the structural protein collagen 6. Substrates other than proteins rapidly came into the purview of PD.…”

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Orientation and Incorporation of Photosystem I in Bioelectronics Devices Enabled by Phage Display

et al. 2017

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Peptide exosite inhibitors of factor VIIa as anticoagulants

Cited by 201 publications

References 41 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

The 99 and 170 Loop-modified Factor VIIa Mutants Show Enhanced Catalytic Activity without Tissue Factor

Orientation and Incorporation of Photosystem I in Bioelectronics Devices Enabled by Phage Display

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