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1dic

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Revision as of 04:15, 30 August 2017

STRUCTURE OF 3,4-DICHLOROISOCOUMARIN-INHIBITED FACTOR D

Structural highlights

1dic is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Activity:	Complement factor D, with EC number 3.4.21.46
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[CFAD_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.

Function

[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

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

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.

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^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Cole LB, Kilpatrick JM, Chu N, Babu YS. Structure of 3,4-dichloroisocoumarin-inhibited factor D. Acta Crystallogr D Biol Crystallogr. 1998 Sep 1;54(Pt 5):711-7. PMID:9757085

1 Structural highlights
2 Disease
3 Function
4 Evolutionary Conservation
5 Publication Abstract from PubMed
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/1dic"

@@ Line 1: / Line 1: @@
 ==STRUCTURE OF 3,4-DICHLOROISOCOUMARIN-INHIBITED FACTOR D==
 <StructureSection load='1dic' size='340' side='right' caption='[[1dic]], [[Resolution|resolution]] 1.80&Aring;' scene=''>
@@ Line 5: / Line 6: @@
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=DIC:3,4-DICHLOROISOCOUMARIN'>DIC</scene>, <scene name='pdbligand=O:OXYGEN+ATOM'>O</scene></td></tr>
 <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Complement_factor_D Complement factor D], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.46 3.4.21.46] </span></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1dic FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1dic OCA], [http://pdbe.org/1dic PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1dic RCSB], [http://www.ebi.ac.uk/pdbsum/1dic PDBsum]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1dic FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1dic OCA], [http://pdbe.org/1dic PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1dic RCSB], [http://www.ebi.ac.uk/pdbsum/1dic PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=1dic ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 19: / Line 20: @@
     <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/chain_selection.php?pdb_ID=2ata ConSurf].
+</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=1dic ConSurf].
 <div style="clear:both"></div>
 <div style="background-color:#fffaf0;">

1dic

From Proteopedia

Revision as of 04:15, 30 August 2017

STRUCTURE OF 3,4-DICHLOROISOCOUMARIN-INHIBITED FACTOR D

Structural highlights

Disease

Function

Evolutionary Conservation

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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