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Structural and kinetic characterization of Porphyromonas gingivalis glutaminyl cyclase

  • Sebastiaan Lamers ORCID logo , Qiaoli Feng , Yili Cheng , Sihong Yu , Bo Sun , Maxwell Lukman , Jie Jiang und David Ruiz-Carrillo ORCID logo EMAIL logo
Veröffentlicht/Copyright: 7. April 2021
Biological Chemistry
Aus der Zeitschrift Biological Chemistry Band 402 Heft 7

Abstract

Porphyromonas gingivalis is a bacterial species known to be involved in the pathogenesis of chronic periodontitis, that more recently has been as well associated with Alzheimer’s disease. P. gingivalis expresses a glutaminyl cyclase (PgQC) whose human ortholog is known to participate in the beta amyloid peptide metabolism. We have elucidated the crystal structure of PgQC at 1.95 Å resolution in unbound and in inhibitor-complexed forms. The structural characterization of PgQC confirmed that PgQC displays a mammalian fold rather than a bacterial fold. Our biochemical characterization indicates that PgQC uses a mammalian-like catalytic mechanism enabled by the residues Asp149, Glu182, Asp183, Asp218, Asp267 and His299. In addition, we could observe that a non-conserved Trp193 may drive differences in the binding affinity of ligands which might be useful for drug development. With a screening of a small molecule library, we have identified a benzimidazole derivative rendering PgQC inhibition in the low micromolar range that might be amenable for further medicinal chemistry development.

Keywords: Alzheimer’s disease; 5,6-dimethylbenzimidazole; glutaminyl cyclase; periodontitis; Porphyromonas gingivalis; pyroglutamate; Rossmann fold
Corresponding author: David Ruiz-Carrillo, Department of Biological Sciences, School of Science, Xi’an Jiaotong-Liverpool University, Suzhou, Jiangsu215123, China, E-mail:

Funding source: Xi’an Jiaotong-Liverpool University

Acknowledgments

The authors thank the support received at the BL17 and BL18U of the Shanghai Synchrotron Radiation research (Qi-Sheng Wang 2018) facility.

  1. Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

  2. Research funding: Research fund of the department of biology of Xi’an Jiaotong-Liverpool University.

  3. Conflict of interest statement: The authors declare no conflicts of interest regarding this article.

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Supplementary Material

The online version of this article offers supplementary material (https://doi.org/10.1515/hsz-2020-0298).

Received: 2020-09-03
Accepted: 2021-03-16
Published Online: 2021-04-07
Published in Print: 2021-06-25

© 2021 Walter de Gruyter GmbH, Berlin/Boston

Artikel in diesem Heft

  1. Frontmatter
  2. Research Articles/Short Communications
  3. Protein Structure and Function
  4. Structural and kinetic characterization of Porphyromonas gingivalis glutaminyl cyclase
  5. Molecular Medicine
  6. Elucidating the anti-biofilm and anti-quorum sensing potential of selenocystine against respiratory tract infections causing bacteria: in vitro and in silico studies
  7. Carotenoids in Sporidiobolus pararoseus ameliorate diabetic nephropathy in mice through attenuating oxidative stress
  8. Cell Biology and Signaling
  9. Berberine improves dietary-induced cardiac remodeling by upregulating Kruppel-like factor 4-dependent mitochondrial function
  10. Decreased level of miR-1301 promotes colorectal cancer progression via activation of STAT3 pathway
  11. JMJD3-regulated expression of IL-6 is involved in the proliferation and chemosensitivity of acute myeloid leukemia cells
  12. Modulation of recombinant human alpha 1 glycine receptor by flavonoids and gingerols
  13. IL-24 inhibits the malignancy of human glioblastoma cells via destabilization of Zeb1
  14. Glycation of benign meningioma cells leads to increased invasion
  15. Proteolysis
  16. Marked difference in efficiency of the digestive enzymes pepsin, trypsin, chymotrypsin, and pancreatic elastase to cleave tightly folded proteins
https://doi.org/10.1515/hsz-2020-0298
Schlagwörter für diesen Artikel
Alzheimer’s disease; 5,6-dimethylbenzimidazole; glutaminyl cyclase; periodontitis; Porphyromonas gingivalis; pyroglutamate; Rossmann fold

Artikel in diesem Heft

  1. Frontmatter
  2. Research Articles/Short Communications
  3. Protein Structure and Function
  4. Structural and kinetic characterization of Porphyromonas gingivalis glutaminyl cyclase
  5. Molecular Medicine
  6. Elucidating the anti-biofilm and anti-quorum sensing potential of selenocystine against respiratory tract infections causing bacteria: in vitro and in silico studies
  7. Carotenoids in Sporidiobolus pararoseus ameliorate diabetic nephropathy in mice through attenuating oxidative stress
  8. Cell Biology and Signaling
  9. Berberine improves dietary-induced cardiac remodeling by upregulating Kruppel-like factor 4-dependent mitochondrial function
  10. Decreased level of miR-1301 promotes colorectal cancer progression via activation of STAT3 pathway
  11. JMJD3-regulated expression of IL-6 is involved in the proliferation and chemosensitivity of acute myeloid leukemia cells
  12. Modulation of recombinant human alpha 1 glycine receptor by flavonoids and gingerols
  13. IL-24 inhibits the malignancy of human glioblastoma cells via destabilization of Zeb1
  14. Glycation of benign meningioma cells leads to increased invasion
  15. Proteolysis
  16. Marked difference in efficiency of the digestive enzymes pepsin, trypsin, chymotrypsin, and pancreatic elastase to cleave tightly folded proteins
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