1dic
From Proteopedia
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'''STRUCTURE OF 3,4-DICHLOROISOCOUMARIN-INHIBITED FACTOR D''' | '''STRUCTURE OF 3,4-DICHLOROISOCOUMARIN-INHIBITED FACTOR D''' | ||
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[[Category: Cole, L B.]] | [[Category: Cole, L B.]] | ||
[[Category: Kilpatrick, J M.]] | [[Category: Kilpatrick, J M.]] | ||
| - | [[Category: | + | [[Category: Complement]] |
| - | [[Category: | + | [[Category: Factor d]] |
| - | [[Category: | + | [[Category: Hydrolase]] |
| - | [[Category: | + | [[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 | + | |
Revision as of 10:52, 2 May 2008
STRUCTURE OF 3,4-DICHLOROISOCOUMARIN-INHIBITED FACTOR D
Overview
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.
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 Fri May 2 13:52:38 2008
