1DIC

STRUCTURE OF 3,4-DICHLOROISOCOUMARIN-INHIBITED FACTOR D

Summary for 1DIC

• Entry DOI: 10.2210/pdb1dic/pdb
• Descriptor: FACTOR D, 3,4-DICHLOROISOCOUMARIN, OXYGEN ATOM, ... (4 entities in total)
• Functional Keywords: serine protease, complement, factor d, hydrolase
• Biological source: Homo sapiens (human)
• Cellular location: Secreted: P00746
• Total number of polymer chains: 1
• Total formula weight: 24685.84

Authors

Cole, L.B.,Kilpatrick, J.M.,Chu, N.,Babu, Y.S. (deposition date: 1998-07-08, release date: 1999-07-22, Last modification date: 2024-11-20)

Primary citation

Cole, L.B.,Kilpatrick, J.M.,Chu, N.,Babu, Y.S.
Structure of 3,4-dichloroisocoumarin-inhibited factor D.
Acta Crystallogr.,Sect.D, 54:711-717, 1998

PubMed Abstract: 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.

PubMed: 9757085
DOI: 10.1107/S0907444997010457

Experimental method

X-RAY DIFFRACTION (1.8 Å)