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| | ==X-ray structure of furin in complex with the inhibitory antibody Nb14== | | ==X-ray structure of furin in complex with the inhibitory antibody Nb14== |
| - | <StructureSection load='5jmo' size='340' side='right' caption='[[5jmo]], [[Resolution|resolution]] 2.00Å' scene=''> | + | <StructureSection load='5jmo' size='340' side='right'caption='[[5jmo]], [[Resolution|resolution]] 2.00Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5jmo]] is a 6 chain structure with sequence from [http://en.wikipedia.org/wiki/Arabian_camel Arabian camel] and [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5JMO OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5JMO FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5jmo]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Camelus_dromedarius Camelus dromedarius], [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5JMO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5JMO FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.998Å</td></tr> |
| - | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=0QE:CHLOROMETHANE'>0QE</scene>, <scene name='pdbligand=AR7:AMINO{[(4S)-4-AMINO-5,5-DIHYDROXYPENTYL]AMINO}METHANIMINIUM'>AR7</scene>, <scene name='pdbligand=DKA:DECANOIC+ACID'>DKA</scene></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0QE:CHLOROMETHANE'>0QE</scene>, <scene name='pdbligand=AR7:AMINO{[(4S)-4-AMINO-5,5-DIHYDROXYPENTYL]AMINO}METHANIMINIUM'>AR7</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=DKA:DECANOIC+ACID'>DKA</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">FURIN, FUR, PACE, PCSK3 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=5jmo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5jmo OCA], [https://pdbe.org/5jmo PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5jmo RCSB], [https://www.ebi.ac.uk/pdbsum/5jmo PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5jmo ProSAT]</span></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Furin Furin], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.75 3.4.21.75] </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=5jmo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5jmo OCA], [http://pdbe.org/5jmo PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5jmo RCSB], [http://www.ebi.ac.uk/pdbsum/5jmo PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5jmo ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/FURIN_HUMAN FURIN_HUMAN]] Furin is likely to represent the ubiquitous endoprotease activity within constitutive secretory pathways and capable of cleavage at the RX(K/R)R consensus motif.<ref>PMID:7690548</ref> | + | [https://www.uniprot.org/uniprot/FURIN_HUMAN FURIN_HUMAN] Furin is likely to represent the ubiquitous endoprotease activity within constitutive secretory pathways and capable of cleavage at the RX(K/R)R consensus motif.<ref>PMID:7690548</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 5jmo" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 5jmo" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Antibody 3D structures|Antibody 3D structures]] |
| | + | *[[Furin|Furin]] |
| | + | *[[3D structures of non-human antibody|3D structures of non-human antibody]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Arabian camel]] | + | [[Category: Camelus dromedarius]] |
| - | [[Category: Furin]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Human]] | + | [[Category: Large Structures]] |
| - | [[Category: Dahms, S O]] | + | [[Category: Synthetic construct]] |
| - | [[Category: Than, M E]] | + | [[Category: Dahms SO]] |
| - | [[Category: Antibody]] | + | [[Category: Than ME]] |
| - | [[Category: Camelid]]
| + | |
| - | [[Category: Complex]]
| + | |
| - | [[Category: Hydrolase-antibody complex]]
| + | |
| - | [[Category: Protease]]
| + | |
| Structural highlights
5jmo is a 6 chain structure with sequence from Camelus dromedarius, Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Method: | X-ray diffraction, Resolution 1.998Å |
| Ligands: | , , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
FURIN_HUMAN Furin is likely to represent the ubiquitous endoprotease activity within constitutive secretory pathways and capable of cleavage at the RX(K/R)R consensus motif.[1]
Publication Abstract from PubMed
Proprotein Convertases (PCs) represent highly selective serine proteases that activate their substrates upon proteolytic cleavage. Their inhibition is a promising strategy for the treatment of cancer and infectious diseases. Inhibitory camelid antibodies were developed, targeting the prototypical PC furin. Kinetic analyses of them revealed an enigmatic non-competitive mechanism, affecting the inhibition of large proprotein-like but not small peptidic substrates. Here we present the crystal structures of furin in complex with the antibody Nb14 and of free Nb14 at resolutions of 2.0 A and 2.3 A, respectively. Nb14 binds at a site distant to the substrate binding pocket to the P-domain of furin. Interestingly, no major conformational changes were observed upon complex formation, neither for the protease nor for the antibody. Inhibition of furin by Nb14 is instead explained by steric exclusion of specific substrate conformers, explaining why Nb14 inhibits the processing of bulky protein substrates but not of small peptide substrates. This mode of action was further supported by modelling studies with the ternary factor X-furin-antibody complex and a mutation that disrupted the interaction interface between furin and the antibody. The observed binding mode of Nb14 suggests a novel approach for the development of highly specific antibody-based proprotein convertase inhibitors.
The structure of a furin-antibody complex explains non-competitive inhibition by steric exclusion of substrate conformers.,Dahms SO, Creemers JW, Schaub Y, Bourenkov GP, Zogg T, Brandstetter H, Than ME Sci Rep. 2016 Sep 27;6:34303. doi: 10.1038/srep34303. PMID:27670069[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Takahashi S, Kasai K, Hatsuzawa K, Kitamura N, Misumi Y, Ikehara Y, Murakami K, Nakayama K. A mutation of furin causes the lack of precursor-processing activity in human colon carcinoma LoVo cells. Biochem Biophys Res Commun. 1993 Sep 15;195(2):1019-26. PMID:7690548 doi:http://dx.doi.org/10.1006/bbrc.1993.2146
- ↑ Dahms SO, Creemers JW, Schaub Y, Bourenkov GP, Zogg T, Brandstetter H, Than ME. The structure of a furin-antibody complex explains non-competitive inhibition by steric exclusion of substrate conformers. Sci Rep. 2016 Sep 27;6:34303. doi: 10.1038/srep34303. PMID:27670069 doi:http://dx.doi.org/10.1038/srep34303
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