1dic
From Proteopedia
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==Overview== | ==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. | 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. | ||
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| + | ==Disease== | ||
| + | Known diseases associated with this structure: Azoospermia OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=400005 400005]], Complement factor D deficiency OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=134350 134350]], Corneal fleck dystrophy OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=609414 609414]], Properdin deficiency, X-linked OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=300383 300383]] | ||
==About this Structure== | ==About this Structure== | ||
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[[Category: serine protease]] | [[Category: serine protease]] | ||
| - | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov | + | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 16:33:05 2007'' |
Revision as of 14:26, 12 November 2007
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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 DIC and O as ligands. Active as Complement factor D, with EC number 3.4.21.46 Structure known Active Site: S1. 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 Nov 12 16:33:05 2007
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
