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1dic
From Proteopedia
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==Overview== | ==Overview== | ||
| - | Factor D (D) is a serine protease essential in the activation of the | + | 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. |
==Disease== | ==Disease== | ||
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[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Babu, Y | + | [[Category: Babu, Y S.]] |
[[Category: Chu, N.]] | [[Category: Chu, N.]] | ||
| - | [[Category: Cole, L | + | [[Category: Cole, L B.]] |
| - | [[Category: Kilpatrick, J | + | [[Category: Kilpatrick, J M.]] |
[[Category: DIC]] | [[Category: DIC]] | ||
[[Category: O]] | [[Category: O]] | ||
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[[Category: serine protease]] | [[Category: serine protease]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 12:16:54 2008'' |
Revision as of 10:16, 21 February 2008
|
STRUCTURE OF 3,4-DICHLOROISOCOUMARIN-INHIBITED FACTOR D
Contents |
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.
Disease
Known diseases associated with this structure: Azoospermia OMIM:[400005], Complement factor D deficiency OMIM:[134350], Corneal fleck dystrophy OMIM:[609414], Properdin deficiency, X-linked OMIM:[300383]
About this Structure
1DIC is a Single protein structure of sequence from Homo sapiens with and as ligands. Active as Complement factor D, with EC number 3.4.21.46 Known structural/functional Site: . 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 Thu Feb 21 12:16:54 2008
Categories: Complement factor D | Homo sapiens | Single protein | Babu, Y S. | Chu, N. | Cole, L B. | Kilpatrick, J M. | DIC | O | Complement | Factor d | Hydrolase | Serine protease
