1dfp: Difference between revisions
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==Overview== | ==Overview== | ||
Factor D (D) is a serine protease, crucial for the activation of the | Factor D (D) is a serine protease, crucial for the activation of the alternative complement pathway. Only a limited number of general serine protease inhibitors are known to inhibit D, most of which covalently bind to the serine hydroxyl of the catalytic triad. The structure of the first enzyme:inhibitor covalent adduct of D with diisopropyl fluorophosphate (DIP:D) to a resolution of 2.4 A is described. The inhibited enzyme is similar in overall structure to the native enzyme and to trypsin, yet exhibits notable differences in the active site. One region of the active site is conserved between D and trypsin with respect to amino-acid sequence and to conformation. Another reflects the amino-acid substitutions and conformational flexibility between these enzymes. The active-site histidine residue is observed in the gauche+ conformation, not the normal gauche- orientation seen in the classic catalytic triad arrangement required for enzymatic activity in serine proteases. Comparisons of the active sites between native D, the DIP:D adduct, and DIP-inhibited trypsin have provided fundamental insights currently being employed in the 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: Narayana, S | [[Category: Narayana, S V.L.]] | ||
[[Category: Volanakis, J | [[Category: Volanakis, J E.]] | ||
[[Category: DFP]] | [[Category: DFP]] | ||
[[Category: complement]] | [[Category: complement]] | ||
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[[Category: serine protease]] | [[Category: serine protease]] | ||
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Revision as of 13:16, 21 February 2008
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FACTOR D INHIBITED BY DIISOPROPYL FLUOROPHOSPHATE
OverviewOverview
Factor D (D) is a serine protease, crucial for the activation of the alternative complement pathway. Only a limited number of general serine protease inhibitors are known to inhibit D, most of which covalently bind to the serine hydroxyl of the catalytic triad. The structure of the first enzyme:inhibitor covalent adduct of D with diisopropyl fluorophosphate (DIP:D) to a resolution of 2.4 A is described. The inhibited enzyme is similar in overall structure to the native enzyme and to trypsin, yet exhibits notable differences in the active site. One region of the active site is conserved between D and trypsin with respect to amino-acid sequence and to conformation. Another reflects the amino-acid substitutions and conformational flexibility between these enzymes. The active-site histidine residue is observed in the gauche+ conformation, not the normal gauche- orientation seen in the classic catalytic triad arrangement required for enzymatic activity in serine proteases. Comparisons of the active sites between native D, the DIP:D adduct, and DIP-inhibited trypsin have provided fundamental insights currently being employed in the design of novel small-molecule pharmaceutical agents capable of modulating the alternative complement pathway.
DiseaseDisease
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 StructureAbout this Structure
1DFP is a Single protein structure of sequence from Homo sapiens with as ligand. Active as Complement factor D, with EC number 3.4.21.46 Known structural/functional Sites: and . Full crystallographic information is available from OCA.
ReferenceReference
Structure of diisopropyl fluorophosphate-inhibited factor D., Cole LB, Chu N, Kilpatrick JM, Volanakis JE, Narayana SV, Babu YS, Acta Crystallogr D Biol Crystallogr. 1997 Mar 1;53(Pt 2):143-50. PMID:15299948
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