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| - | [[Image:1dic.gif|left|200px]] | + | {{Seed}} |
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| | {{STRUCTURE_1dic| PDB=1dic | SCENE= }} | | {{STRUCTURE_1dic| PDB=1dic | SCENE= }} |
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| - | '''STRUCTURE OF 3,4-DICHLOROISOCOUMARIN-INHIBITED FACTOR D'''
| + | ===STRUCTURE OF 3,4-DICHLOROISOCOUMARIN-INHIBITED FACTOR D=== |
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| - | ==Overview==
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| - | Factor D (D) is a serine protease essential in the activation of the alternative complement pathway. Only a few of the common serine protease inhibitors inhibit D, binding covalently to the serine hydroxyl of the catalytic triad. 3,4-Dichloroisocoumarin (DCI) is a mechanism-based inhibitor which inhibits most serine proteases and many esterases, including D. The structure of the enzyme:inhibitor covalent adduct of D with DCI, DCI:D, to a resolution of 1.8 A is described, which represents the first structural analysis of D with a mechanism-based inhibitor. The side chain of the ring-opened DCI moiety of the protein adduct undergoes chemical modification in the buffered solution, resulting in the formation of an alpha-hydroxy acid moiety through the nucleophilic substitution of both Cl atoms. The inhibited enzyme is similar in overall structure to the native enzyme, as well as to a variety of isocoumarin-inhibited trypsin and porcine pancreatic elastase (PPE) structures, yet notable differences are observed in the active site and binding mode of these small-molecule inhibitors. One region of the active site (residues 189-195) is relatively conserved between factor D, trypsin, and elastase with respect to amino-acid sequence and to conformation. Another region (residues 214-220) reflects the amino-acid substitutions and conformational flexibility between these enzymes. The carbonyl O atom of the DCI moiety was found to be oriented away from the oxyanion hole, which greatly contributes to the stability of the DCI:D adduct. The comparisons of the active sites between native factor D, DCI-inhibited factor D, and various inhibited trypsin and elastase (PPE) molecules are providing the chemical bases directing our design of novel, small-molecule pharmaceutical agents capable of modulating the alternative complement pathway.
| + | The line below this paragraph, {{ABSTRACT_PUBMED_9757085}}, adds the Publication Abstract to the page |
| | + | (as it appears on PubMed at http://www.pubmed.gov), where 9757085 is the PubMed ID number. |
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| | + | {{ABSTRACT_PUBMED_9757085}} |
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| | ==About this Structure== | | ==About this Structure== |
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| | [[Category: Hydrolase]] | | [[Category: Hydrolase]] |
| | [[Category: Serine protease]] | | [[Category: Serine protease]] |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri May 2 13:52:38 2008'' | + | |
| | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jun 30 23:06:21 2008'' |
Revision as of 20:06, 30 June 2008
Template:STRUCTURE 1dic
STRUCTURE OF 3,4-DICHLOROISOCOUMARIN-INHIBITED FACTOR D
Template:ABSTRACT PUBMED 9757085
About this Structure
1DIC is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Structure of 3,4-dichloroisocoumarin-inhibited factor D., Cole LB, Kilpatrick JM, Chu N, Babu YS, Acta Crystallogr D Biol Crystallogr. 1998 Sep 1;54(Pt 5):711-7. PMID:9757085
Page seeded by OCA on Mon Jun 30 23:06:21 2008
