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== | ==FACTOR D INHIBITED BY DIISOPROPYL FLUOROPHOSPHATE== | ||
<StructureSection load='1dfp' size='340' side='right'caption='[[1dfp]], [[Resolution|resolution]] 2.40Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[1dfp]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1DFP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1DFP FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.4Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DFP:DIISOPROPYL+PHOSPHONATE'>DFP</scene></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1dfp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1dfp OCA], [https://pdbe.org/1dfp PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1dfp RCSB], [https://www.ebi.ac.uk/pdbsum/1dfp PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1dfp ProSAT]</span></td></tr> | |||
</table> | |||
== Disease == | |||
[https://www.uniprot.org/uniprot/CFAD_HUMAN CFAD_HUMAN] Defects in CFD are the cause of complement factor D deficiency (CFDD) [MIM:[https://omim.org/entry/613912 613912]. CFDD is an immunologic disorder characterized by increased susceptibility to bacterial infections, particularly Neisseria infections, due to a defect in the alternative complement pathway. | |||
== Function == | |||
[https://www.uniprot.org/uniprot/CFAD_HUMAN CFAD_HUMAN] Factor D cleaves factor B when the latter is complexed with factor C3b, activating the C3bbb complex, which then becomes the C3 convertase of the alternate pathway. Its function is homologous to that of C1s in the classical pathway. | |||
== Evolutionary Conservation == | |||
[[Image:Consurf_key_small.gif|200px|right]] | |||
Check<jmol> | |||
<jmolCheckbox> | |||
<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/df/1dfp_consurf.spt"</scriptWhenChecked> | |||
<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked> | |||
<text>to colour the structure by Evolutionary Conservation</text> | |||
</jmolCheckbox> | |||
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1dfp ConSurf]. | |||
<div style="clear:both"></div> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
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. | 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. | ||
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<ref>PMID:15299948</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 1dfp" style="background-color:#fffaf0;"></div> | |||
== | ==See Also== | ||
*[[Acetylcholinesterase 3D structures|Acetylcholinesterase 3D structures]] | |||
[[ | *[[Complement factor 3D structures|Complement factor 3D structures]] | ||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: Babu | [[Category: Babu YS]] | ||
[[Category: Chu | [[Category: Chu N]] | ||
[[Category: Cole | [[Category: Cole LB]] | ||
[[Category: Kilpatrick | [[Category: Kilpatrick JM]] | ||
[[Category: Narayana | [[Category: Narayana SVL]] | ||
[[Category: Volanakis | [[Category: Volanakis JE]] | ||
Latest revision as of 02:53, 21 November 2024
FACTOR D INHIBITED BY DIISOPROPYL FLUOROPHOSPHATEFACTOR D INHIBITED BY DIISOPROPYL FLUOROPHOSPHATE
Structural highlights
DiseaseCFAD_HUMAN Defects in CFD are the cause of complement factor D deficiency (CFDD) [MIM:613912. CFDD is an immunologic disorder characterized by increased susceptibility to bacterial infections, particularly Neisseria infections, due to a defect in the alternative complement pathway. FunctionCFAD_HUMAN Factor D cleaves factor B when the latter is complexed with factor C3b, activating the C3bbb complex, which then becomes the C3 convertase of the alternate pathway. Its function is homologous to that of C1s in the classical pathway. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedFactor 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. 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[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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