Inhibitor binding to matrix metalloproteinases /
Reprolysins and matrix metalloproteinases are both members of the MB clan of the metallopeptidase class of enzymes, which cleave components of the extracellular matrix. Snake reprolysins are active at the site of envenomation and are stored in the presence of reversible inhibitors whereas matrix met...
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| Format: | Thesis Book |
| Language: | English |
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[Place of publication not identified] :
[publisher not identified] ;
1999.
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| Subjects: | |
| Online Access: | http://proxy.library.tamu.edu/login?url=http://proquest.umi.com/pqdweb?did=730318871&sid=1&Fmt=2&clientId=2945&RQT=309&VName=PQD |
| Summary: | Reprolysins and matrix metalloproteinases are both members of the MB clan of the metallopeptidase class of enzymes, which cleave components of the extracellular matrix. Snake reprolysins are active at the site of envenomation and are stored in the presence of reversible inhibitors whereas matrix metalloproteinases are inactive prognoses until specifically activated. Reprolysins have defense and digestive functions while matrix metalloproteinases are implicated in physiological and pathological processes. Since matrix metalloproteinases have been implicated in degenerative processes such as tumor cell invasion, metastasis, and arthritis, specific metalloproteinase inhibitors have been used to block their activity. The crystal structure of the potent antitumor drug Batimastat (BB-94) with a snake reprolysin (Ht-d) was determined at 2.0 A resolution. The BB-94 structure exhibits an unexpected binding geometry, with the thiophene ring deeply inserted into the primary specificity site. This unprecedented binding geometry dramatizes the significance of the cavernous primary specificity site, pointing the way for the design of a new generation of potential anti-tumor drugs. A theoretical study was performed on the structure of both native and inhibited Ht-d. Energy maps calculated by program GRID allowed localization and characterization of the pockets S1-S3 and S1'-S3' in the enzyme. Characterization of active site pockets was extended to neutrophil collagenase, fibroblast collagenase, stromelysin 1 and 2. Thirty residues of the Ht-d propeptide were modeled into Ht-d, giving insight to the mechanism of natural inhibition in metalloproteinase prognoses. Kinetic measurements of Ht-d inhibition by a series of synthetic peptides show the crucial role of cysteine and adjacent residues in the specificity of Ht-d propeptide. This study suggests the structural link between Ht-d and mammalian metalloproteinases. The crystal structure of the catalytic domain of recombinant mouse collagenase-3 (MMP-13), completed to the hydroxamate inhibitor (RS-113456), was determined at 2.3 A resolution. The structure illuminates atomic details of the interactions of the zinc ion with functional groups in the active sites emphasizing the role of zinc libation and of the very voluminous hydrophobic P1' group in the potency of the inhibitor. The structure provides insight into the specificity of this enzyme, facilitating design of specific inhibitors to target various diseases. |
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| Item Description: | Vita. "Major Subject: Biochemistry". |
| Physical Description: | xi, 93 leaves : illustrations ; 28 cm. Issued also on microfiche from University Microfilm Inc. |
| Bibliography: | Includes bibliographical references (leaves 72-90). |