Structural characterization of a venom metalloproteinase, Atrolysin C (form d), and two inhibitor complexes /
The hemorrhagic toxin atrolysin C form d (Ht-d, EC 3.4.24.42)
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| Format: | Thesis Book |
| Language: | English |
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[Place of publication not identified] :
[publisher not identified] ;
1996.
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| Online Access: | http://proxy.library.tamu.edu/login?url=http://proquest.umi.com/pqdweb?did=739668161&sid=1&Fmt=2&clientId=2945&RQT=309&VName=PQD |
| Summary: | The hemorrhagic toxin atrolysin C form d (Ht-d, EC 3.4.24.42) from the western diamondback rattle snake Crotalus atrox is a member of the zinc endo-metalloproteinase family. Studies showed that Ht-d has similar biological functions to those of matrix metalloproteinases which are believed to play an important role in pathological conditions such as arthritis and tumor invasion. Ht-d is a 24 kDa protein and contains a single catalytic domain. We have determined the three- dimensional crystal structures of Ht-d and two inhibited complexes at high resolution by X-ray diffraction analysis. The Ht-d structure reveals a tetrahedral zinc binding active site with a consensus zinc binding sequence HEXXHXXGXXH. The major topological structure of Ht-d, including five []-sheet and three major helixes, is shared with those of matrix metalloproteinases despite their very low sequence homology. The complex structures of Ht-d and its inhibitors illuminate the inhibitor binding mode, showing that a primary specific pocket in the active site of Ht-d is essential for the inhibitor binding. Weak van der Waals interactions of inhibitors with the enzyme play a dominant role in the specificity of the substrate binding. Studies also showed that the active site of Ht-d is very similar to stromelysin, a member of the matrix metalloproteinase (MMP) family and a key enzyme related to many diseases. The detailed description of protein-inhibitor interactions present in this research will aid in the design of compounds that selectively inhibit matrix metalloproteinases. Such inhibitors will be useful for examining the function of MMPs in pathological processes and may be used as potential drugs to treat many diseases caused by MMPs, such as arthritis and various cancers. |
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| Item Description: | Vita. "Major Subject: Biochemistry". |
| Physical Description: | xiii, 178 leaves : illustrations ; 28 cm. Issued also on microfiche from University Microfilms Inc. |
| Bibliography: | Includes bibliographical references: pages 170-177. |