Structure of the catalytic domain of the Tannerella forsythia matrix metallopeptidase karilysin in complex with a tetrapeptidic inhibitor

Tibisay Guevara; Miroslaw Ksiazek; Peter Durand Skottrup; Núria Cerdà-Costa; Sergio Trillo-Muyo; Inaki de Diego; Erik Skjold Riise; Jan Potempa; F. Xavier  Gomis-Rüth

doi:10.1107/S174430911300739

Structure of the catalytic domain of the Tannerella forsythia matrix metallopeptidase karilysin in complex with a tetrapeptidic inhibitor

Tibisay Guevara, Miroslaw Ksiazek, Peter Durand Skottrup, Núria Cerdà-Costa, Sergio Trillo-Muyo, Inaki de Diego, Erik Skjold Riise, Jan Potempa, F. Xavier Gomis-Rüth

8 Citations (Scopus)

Abstract

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 α-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.

Original language	English
Journal	Acta Crystallographica. Section F: Structural Biology and Crystallization Communications Online
Volume	69
Issue number	Pt 5
Pages (from-to)	472-6
ISSN	1744-3091
DOIs	https://doi.org/10.1107/S174430911300739
Publication status	Published - May 2013

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Guevara, T., Ksiazek, M., Skottrup, P. D., Cerdà-Costa, N., Trillo-Muyo, S., de Diego, I., Riise, E. S., Potempa, J., & Gomis-Rüth, F. X. (2013). Structure of the catalytic domain of the Tannerella forsythia matrix metallopeptidase karilysin in complex with a tetrapeptidic inhibitor. Acta Crystallographica. Section F: Structural Biology and Crystallization Communications Online, 69(Pt 5), 472-6. https://doi.org/10.1107/S174430911300739

Structure of the catalytic domain of the Tannerella forsythia matrix metallopeptidase karilysin in complex with a tetrapeptidic inhibitor. / Guevara, Tibisay; Ksiazek, Miroslaw; Skottrup, Peter Durand et al.
In: Acta Crystallographica. Section F: Structural Biology and Crystallization Communications Online, Vol. 69, No. Pt 5, 05.2013, p. 472-6.

Research output: Contribution to journal › Journal article › Research › peer-review

Guevara, T, Ksiazek, M, Skottrup, PD, Cerdà-Costa, N, Trillo-Muyo, S, de Diego, I, Riise, ES, Potempa, J & Gomis-Rüth, FX 2013, 'Structure of the catalytic domain of the Tannerella forsythia matrix metallopeptidase karilysin in complex with a tetrapeptidic inhibitor', Acta Crystallographica. Section F: Structural Biology and Crystallization Communications Online, vol. 69, no. Pt 5, pp. 472-6. https://doi.org/10.1107/S174430911300739

Guevara T, Ksiazek M, Skottrup PD, Cerdà-Costa N, Trillo-Muyo S, de Diego I et al. Structure of the catalytic domain of the Tannerella forsythia matrix metallopeptidase karilysin in complex with a tetrapeptidic inhibitor. Acta Crystallographica. Section F: Structural Biology and Crystallization Communications Online. 2013 May;69(Pt 5):472-6. doi: 10.1107/S174430911300739

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title = "Structure of the catalytic domain of the Tannerella forsythia matrix metallopeptidase karilysin in complex with a tetrapeptidic inhibitor",

abstract = "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 α-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.",

author = "Tibisay Guevara and Miroslaw Ksiazek and Skottrup, {Peter Durand} and N{\'u}ria Cerd{\`a}-Costa and Sergio Trillo-Muyo and {de Diego}, Inaki and Riise, {Erik Skjold} and Jan Potempa and Gomis-R{\"u}th, {F. Xavier}",

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AU - Guevara, Tibisay

AU - Ksiazek, Miroslaw

AU - Skottrup, Peter Durand

AU - Cerdà-Costa, Núria

AU - Trillo-Muyo, Sergio

AU - de Diego, Inaki

AU - Riise, Erik Skjold

AU - Potempa, Jan

AU - Gomis-Rüth, F. Xavier

PY - 2013/5

Y1 - 2013/5

N2 - 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 α-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.

AB - 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 α-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.

U2 - 10.1107/S174430911300739

DO - 10.1107/S174430911300739

M3 - Journal article

SN - 1744-3091

VL - 69

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EP - 476

JO - Acta Crystallographica. Section F: Structural Biology and Crystallization Communications Online

JF - Acta Crystallographica. Section F: Structural Biology and Crystallization Communications Online

IS - Pt 5

ER -

Structure of the catalytic domain of the Tannerella forsythia matrix metallopeptidase karilysin in complex with a tetrapeptidic inhibitor

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