4in9

From Proteopedia

(Difference between revisions)

Current revision

Structure of karilysin MMP-like catalytic domain in complex with inhibitory tetrapeptide SWFP

Structural highlights

4in9 is a 2 chain structure with sequence from Tannerella forsythia 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 1.55Å
Ligands:	, , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

KLY_TANFA Metalloprotease able to cleave casein, gelatin, elastin, fibrinogen and fibronectin. Shows exclusive preference for hydrophobic residues, especially Leu, Tyr and Met, at the P1' position of substrates, and for Pro or Ala at P3. Can efficiently cleave the antimicrobial peptide LL-37 which is a component of the immune system, leading to a significant reduction of its bactericidal activity. Is also able to inhibit all pathways of the human complement system. The classical and lectin complement pathways are inhibited because of the efficient degradation of mannose-binding lectin, ficolin-2, ficolin-3, and C4 by karilysin, whereas inhibition of the terminal pathway is caused by cleavage of C5. Thus, karilysin appears to be a major virulence factor of T.forsythia that contributes to evasion of the human immune response and periodontal disease. Seems to act synergistically with gingipains from the periodontal pathogen P.gingivalis present at the same sites of infection.^[1] ^[2] ^[3] ^[4]

Publication Abstract from PubMed

Karilysin is the only metallopeptidase identified as a virulence factor in the odontopathogen Tannerella forsythia owing to its deleterious effect on the host immune response during bacterial infection. The very close structural and sequence-based similarity of its catalytic domain (Kly18) to matrix metalloproteinases suggests that karilysin was acquired by horizontal gene transfer from an animal host. Previous studies by phage display identified peptides with the consensus sequence XWFPXXXGGG (single-letter amino-acid codes; X represents any residue) as karilysin inhibitors with low-micromolar binding affinities. Subsequent refinement revealed that inhibition comparable to that of longer peptides could be achieved using the tetrapeptide SWFP. To analyze its binding, the high-resolution crystal structure of the complex between Kly18 and SWFP was determined and it was found that the peptide binds to the primed side of the active-site cleft in a substrate-like manner. The catalytic zinc ion is clamped by the alpha-amino group and the carbonyl O atom of the serine, thus distantly mimicking the general manner of binding of hydroxamate inhibitors to metallopeptidases and contributing, together with three zinc-binding histidines from the protein scaffold, to an octahedral-minus-one metal-coordination sphere. The tryptophan side chain penetrates the deep partially water-filled specificity pocket of Kly18. Together with previous serendipitous product complexes of Kly18, the present results provide the structural determinants of inhibition of karilysin and open the field for the design of novel inhibitory strategies aimed at the treatment of human periodontal disease based on a peptidic hit molecule.

Structure of the catalytic domain of the Tannerella forsythia matrix metallopeptidase karilysin in complex with a tetrapeptidic inhibitor.,Guevara T, Ksiazek M, Skottrup PD, Cerda-Costa N, Trillo-Muyo S, de Diego I, Riise E, Potempa J, Gomis-Ruth FX Acta Crystallogr Sect F Struct Biol Cryst Commun. 2013 May;69(Pt 5):472-6. doi:, 10.1107/S1744309113007392. Epub 2013 Apr 27. PMID:23695557^[5]

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

References

↑ Karim AY, Kulczycka M, Kantyka T, Dubin G, Jabaiah A, Daugherty PS, Thogersen IB, Enghild JJ, Nguyen KA, Potempa J. A novel matrix metalloprotease-like enzyme (karilysin) of the periodontal pathogen Tannerella forsythia ATCC 43037. Biol Chem. 2010 Jan;391(1):105-17. PMID:19919176 doi:10.1515/BC.2010.009
↑ Koziel J, Karim AY, Przybyszewska K, Ksiazek M, Rapala-Kozik M, Nguyen KA, Potempa J. Proteolytic inactivation of LL-37 by karilysin, a novel virulence mechanism of Tannerella forsythia. J Innate Immun. 2010;2(3):288-93. Epub 2010 Feb 4. PMID:20375548 doi:10.1159/000281881
↑ Cerda-Costa N, Guevara T, Karim AY, Ksiazek M, Nguyen KA, Arolas JL, Potempa J, Gomis-Ruth FX. The structure of the catalytic domain of Tannerella forsythia karilysin reveals it is a bacterial xenologue of animal matrix metalloproteinases. Mol Microbiol. 2011 Jan;79(1):119-132. doi:, 10.1111/j.1365-2958.2010.07434.x. Epub 2010 Nov 2. PMID:21166898 doi:10.1111/j.1365-2958.2010.07434.x
↑ Jusko M, Potempa J, Karim AY, Ksiazek M, Riesbeck K, Garred P, Eick S, Blom AM. A metalloproteinase karilysin present in the majority of Tannerella forsythia isolates inhibits all pathways of the complement system. J Immunol. 2012 Mar 1;188(5):2338-49. doi: 10.4049/jimmunol.1101240. Epub 2012, Jan 27. PMID:22287711 doi:http://dx.doi.org/10.4049/jimmunol.1101240
↑ Guevara T, Ksiazek M, Skottrup PD, Cerda-Costa N, Trillo-Muyo S, de Diego I, Riise E, Potempa J, Gomis-Ruth FX. Structure of the catalytic domain of the Tannerella forsythia matrix metallopeptidase karilysin in complex with a tetrapeptidic inhibitor. Acta Crystallogr Sect F Struct Biol Cryst Commun. 2013 May;69(Pt 5):472-6. doi:, 10.1107/S1744309113007392. Epub 2013 Apr 27. PMID:23695557 doi:10.1107/S1744309113007392

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4in9"

@@ Line 4: / Line 4: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[4in9]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Tannerella_forsythia Tannerella forsythia] 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=4IN9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4IN9 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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]] 1.55&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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=4in9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4in9 OCA], [https://pdbe.org/4in9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4in9 RCSB], [https://www.ebi.ac.uk/pdbsum/4in9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4in9 ProSAT]</span></td></tr>
 </table>

4in9

From Proteopedia

Current revision

Structure of karilysin MMP-like catalytic domain in complex with inhibitory tetrapeptide SWFP

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

Personal tools

Navigation

Search

Toolbox