1dic

From Proteopedia

Revision as of 12:34, 18 December 2007

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.

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 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

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