Proteopedia

7zbv

Crystal structure of the peptidase domain of collagenase G from Clostridium histolyticum in complex with a diphosphonate-based inhibitorCrystal structure of the peptidase domain of collagenase G from Clostridium histolyticum in complex with a diphosphonate-based inhibitor

Structural highlights

7zbv is a 1 chain structure with sequence from Hathewaya histolytica. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 1.95Å
Ligands:, , ,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

COLG_HATHI Clostridial collagenases are among the most efficient degraders of eukaryotic collagen known; saprophytes use collagen as a carbon source while pathogens additionally digest collagen to aid in host colonization. Has both tripeptidylcarboxypeptidase on Gly-X-Y and endopeptidase activities; the endopeptidase cuts within the triple helix region of collagen while tripeptidylcarboxypeptidase successively digests the exposed ends, thus clostridial collagenases can digest large sections of collagen (PubMed:3002446). Active on soluble type I collagen, insoluble collagen, azocoll, soluble PZ-peptide (all collagenase substrates) and gelatin (PubMed:9922257). The full-length protein has collagenase activity, while the in vivo derived C-terminally truncated shorter versions only act on gelatin (PubMed:9922257). In vitro digestion of soluble calf skin collagen fibrils requires both ColG and ColH; ColG forms missing the second collagen-binding domain are also synergistic with ColH, although their overall efficiency is decreased (PubMed:18374061, PubMed:22099748). The activator domain (residues 119-388) and catalytic subdomain (389-670) open and close around substrate using a Gly-rich hinge (387-397), allowing digestion when the protein is closed (PubMed:21947205, PubMed:23703618). Binding of collagen requires Ca(2+) and is inhibited by EGTA; the collagen-binding domain (CBD, S3a plus S3b) specifically recognizes the triple-helical conformation made by 3 collagen protein chains in the triple-helical region (PubMed:11121400). Isolated CBD (S3a plus S3b) binds collagen fibrils and sheets of many tissues (PubMed:11913772).[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11]

Publication Abstract from PubMed

In view of the worldwide antimicrobial resistance (AMR) threat, new bacterial targets and anti-infective agents are needed. Since important roles in bacterial pathogenesis have been demonstrated for the collagenase H and G (ColH and ColG) from Clostridium histolyticum, collagenase Q1 and A (ColQ1 and ColA) from Bacillus cereus represent attractive antivirulence targets. Furthermore, repurposing FDA-approved drugs may assist to tackle the AMR crisis and was addressed in this work. Here, we report on the discovery of two potent and chemically stable bacterial collagenase inhibitors: synthesized and FDA-approved diphosphonates and hydroxamates. Both classes showed high in vitro activity against the clostridial and bacillary collagenases. The potent diphosphonates reduced B. cereus-mediated detachment and death of cells and Galleria mellonella larvae. The hydroxamates were also tested in a similar manner; they did not have an effect in infection models. This might be due to their fast binding kinetics to bacterial collagenases.

Discovery and Characterization of Synthesized and FDA-Approved Inhibitors of Clostridial and Bacillary Collagenases.,Alhayek A, Abdelsamie AS, Schonauer E, Camberlein V, Hutterer E, Posselt G, Serwanja J, Blochl C, Huber CG, Haupenthal J, Brandstetter H, Wessler S, Hirsch AKH J Med Chem. 2022 Oct 13;65(19):12933-12955. doi: 10.1021/acs.jmedchem.2c00785., Epub 2022 Sep 26. PMID:36154055[12]

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

See Also

References

  1. ↑ Matsushita O, Koide T, Kobayashi R, Nagata K, Okabe A. Substrate recognition by the collagen-binding domain of Clostridium histolyticum class I collagenase. J Biol Chem. 2001 Mar 23;276(12):8761-70. doi: 10.1074/jbc.M003450200. Epub 2000 , Dec 19. PMID:11121400 doi:http://dx.doi.org/10.1074/jbc.M003450200
  2. ↑ Toyoshima T, Matsushita O, Minami J, Nishi N, Okabe A, Itano T. Collagen-binding domain of a Clostridium histolyticum collagenase exhibits a broad substrate spectrum both in vitro and in vivo. Connect Tissue Res. 2001;42(4):281-90. doi: 10.3109/03008200109016842. PMID:11913772 doi:http://dx.doi.org/10.3109/03008200109016842
  3. ↑ McCarthy RC, Spurlin B, Wright MJ, Breite AG, Sturdevant LK, Dwulet CS, Dwulet FE. Development and characterization of a collagen degradation assay to assess purified collagenase used in islet isolation. Transplant Proc. 2008 Mar;40(2):339-42. doi: 10.1016/j.transproceed.2008.01.041. PMID:18374061 doi:http://dx.doi.org/10.1016/j.transproceed.2008.01.041
  4. ↑ Eckhard U, Schonauer E, Ducka P, Briza P, Nuss D, Brandstetter H. Biochemical characterization of the catalytic domains of three different Clostridial collagenases. Biol Chem. 2009 Jan;390(1):11-8. doi: 10.1515/BC.2009.004. PMID:18937627 doi:http://dx.doi.org/10.1515/BC.2009.004
  5. ↑ Eckhard U, Schonauer E, Nuss D, Brandstetter H. Structure of collagenase G reveals a chew-and-digest mechanism of bacterial collagenolysis. Nat Struct Mol Biol. 2011 Sep 25;18(10):1109-14. doi: 10.1038/nsmb.2127. PMID:21947205 doi:10.1038/nsmb.2127
  6. ↑ Breite AG, McCarthy RC, Dwulet FE. Characterization and functional assessment of Clostridium histolyticum class I (C1) collagenases and the synergistic degradation of native collagen in enzyme mixtures containing class II (C2) collagenase. Transplant Proc. 2011 Nov;43(9):3171-5. doi: 10.1016/j.transproceed.2011.09.059. PMID:22099748 doi:http://dx.doi.org/10.1016/j.transproceed.2011.09.059
  7. ↑ Eckhard U, Schonauer E, Brandstetter H. Structural basis for activity regulation and substrate preference of clostridial collagenases G, H, and T. J Biol Chem. 2013 May 23. PMID:23703618 doi:10.1074/jbc.M112.448548
  8. ↑ Eckhard U, Huesgen PF, Brandstetter H, Overall CM. Proteomic protease specificity profiling of clostridial collagenases reveals their intrinsic nature as dedicated degraders of collagen. J Proteomics. 2014 Apr 4;100:102-14. doi: 10.1016/j.jprot.2013.10.004. Epub 2013 , Oct 11. PMID:24125730 doi:http://dx.doi.org/10.1016/j.jprot.2013.10.004
  9. ↑ Schonauer E, Kany AM, Haupenthal J, Husecken K, Hoppe IJ, Voos K, Yahiaoui S, Elsasser B, Ducho C, Brandstetter H, Hartmann RW. Discovery of a Potent Inhibitor Class with High Selectivity toward Clostridial Collagenases. J Am Chem Soc. 2017 Sep 13;139(36):12696-12703. doi: 10.1021/jacs.7b06935. Epub, 2017 Aug 31. PMID:28820255 doi:http://dx.doi.org/10.1021/jacs.7b06935
  10. ↑ Mookhtiar KA, Steinbrink DR, Van Wart HE. Mode of hydrolysis of collagen-like peptides by class I and class II Clostridium histolyticum collagenases: evidence for both endopeptidase and tripeptidylcarboxypeptidase activities. Biochemistry. 1985 Nov 5;24(23):6527-33. doi: 10.1021/bi00344a033. PMID:3002446 doi:http://dx.doi.org/10.1021/bi00344a033
  11. ↑ Matsushita O, Jung CM, Katayama S, Minami J, Takahashi Y, Okabe A. Gene duplication and multiplicity of collagenases in Clostridium histolyticum. J Bacteriol. 1999 Feb;181(3):923-33. doi: 10.1128/JB.181.3.923-933.1999. PMID:9922257 doi:http://dx.doi.org/10.1128/JB.181.3.923-933.1999
  12. ↑ Alhayek A, Abdelsamie AS, Schonauer E, Camberlein V, Hutterer E, Posselt G, Serwanja J, Blochl C, Huber CG, Haupenthal J, Brandstetter H, Wessler S, Hirsch AKH. Discovery and Characterization of Synthesized and FDA-Approved Inhibitors of Clostridial and Bacillary Collagenases. J Med Chem. 2022 Oct 13;65(19):12933-12955. doi: 10.1021/acs.jmedchem.2c00785., Epub 2022 Sep 26. PMID:36154055 doi:http://dx.doi.org/10.1021/acs.jmedchem.2c00785

7zbv, resolution 1.95Å

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