PDBsum entry 1cvr

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Hydrolase/hydrolase inhibitor PDB id
Protein chain
432 a.a. *
_ZN ×2
_CA ×6
Waters ×322
* Residue conservation analysis
PDB id:
Name: Hydrolase/hydrolase inhibitor
Title: Crystal structure of the arg specific cysteine proteinase gi (rgpb)
Structure: Gingipain r. Chain: a. Synonym: rgpb. Engineered: yes
Source: Porphyromonas gingivalis. Organism_taxid: 837
Biol. unit: Trimer (from PQS)
2.00Å     R-factor:   0.163     R-free:   0.207
Authors: A.Eichinger,H.-G.Beisel
Key ref:
A.Eichinger et al. (1999). Crystal structure of gingipain R: an Arg-specific bacterial cysteine proteinase with a caspase-like fold. EMBO J, 18, 5453-5462. PubMed id: 10523290 DOI: 10.1093/emboj/18.20.5453
24-Aug-99     Release date:   01-Mar-00    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P95493  (CPG2_PORGI) -  Gingipain R2
736 a.a.
432 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 13 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: E.C.  - Gingipain R.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Cleavage of proteins, including collagens and immunoglobulins, with a preference for Arg in P1, and hydrophobic residues in P2 and P3.
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     proteolysis   1 term 
  Biochemical function     peptidase activity     2 terms  


DOI no: 10.1093/emboj/18.20.5453 EMBO J 18:5453-5462 (1999)
PubMed id: 10523290  
Crystal structure of gingipain R: an Arg-specific bacterial cysteine proteinase with a caspase-like fold.
A.Eichinger, H.G.Beisel, U.Jacob, R.Huber, F.J.Medrano, A.Banbula, J.Potempa, J.Travis, W.Bode.
Gingipains are cysteine proteinases acting as key virulence factors of the bacterium Porphyromonas gingivalis, the major pathogen in periodontal disease. The 1.5 and 2.0 A crystal structures of free and D-Phe-Phe-Arg-chloromethylketone-inhibited gingipain R reveal a 435-residue, single-polypeptide chain organized into a catalytic and an immunoglobulin-like domain. The catalytic domain is subdivided into two subdomains comprising four- and six-stranded beta-sheets sandwiched by alpha-helices. Each subdomain bears topological similarities to the p20-p10 heterodimer of caspase-1. The second subdomain harbours the Cys-His catalytic diad and a nearby Glu arranged around the S1 specificity pocket, which carries an Asp residue to enforce preference for Arg-P1 residues. This gingipain R structure is an excellent template for the rational design of drugs with a potential to cure and prevent periodontitis. Here we show the binding mode of an arginine-containing inhibitor in the active-site, thus identifying major interaction sites defining a suitable pharmacophor.
  Selected figure(s)  
Figure 3.
Figure 3 Interaction of the D-Phe -L-Phe -L-Arg methylene inhibitor with the RgpB active-site. The active-site region of RgpB, besides a few important residues (green) mainly represented by the ribbon-like backbone (pink), is shown in standard orientation (obtained from the front view, Figure 1, upon a 90 rotation about a horizontal axis). The inhibitor chain (yellow stick model) covalently linked via its methylene group to Cys244 S (centre, right) runs from left to right, with its Arg-P1 side chain reaching back into the S1 pocket. The imidazole side chain of His211 and the carboxylate of Glu152 are arranged on the molecular surface (bottom) opposite to Cys244. The figure was prepared with Insight II.
Figure 6.
Figure 6 Comparison of the RgpB catalytic domain (top, in stereo, red, yellow and blue) and the caspase-3 tetramer (bottom, in stereo, with both p17 and p12 peptides given in red and blue; Protein Data Bank code 1PAU; Rotonda et al., 1996). The catalytic residues are shown as orange and yellow stick models. The caspase is presented in such an orientation that its left-side p17 -p12 heterodimer half superimposes with the 'active' RgpB B-subdomain. Both RgpB subdomains are related to one another by a vertical axis with an 160 rotational and an 15 translational component arranged within the plane, while the exact 2-fold rotation axis of caspase-3 relating both heterodimers stands vertically on the plane. The figure was prepared with BOBSCRIPT (Kraulis, 1991) and rendered with RASTER3D (Merrit and Murphy, 1994).
  The above figures are reprinted from an Open Access publication published by Macmillan Publishers Ltd: EMBO J (1999, 18, 5453-5462) copyright 1999.  
  Figures were selected by the author.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21104192 K.Prymula, T.Jadczyk, and I.Roterman (2011).
Catalytic residues in hydrolases: analysis of methods designed for ligand-binding site prediction.
  J Comput Aided Mol Des, 25, 117-133.  
21181719 M.Shokhen, N.Khazanov, and A.Albeck (2011).
The mechanism of papain inhibition by peptidyl aldehydes.
  Proteins, 79, 975-985.  
21244528 Y.Y.Chen, B.Peng, Q.Yang, M.D.Glew, P.D.Veith, K.J.Cross, K.N.Goldie, D.Chen, N.O'Brien-Simpson, S.G.Dashper, and E.C.Reynolds (2011).
The outer membrane protein LptO is essential for the O-deacylation of LPS and the co-ordinated secretion and attachment of A-LPS and CTD proteins in Porphyromonas gingivalis.
  Mol Microbiol, 79, 1380-1401.  
20957091 D.Kim, and D.S.Lee (2010).
A Computational Simulation Study of Benzamidine Derivatives Binding to Arginine-Specific Gingipain (HRgpA) from Periodontopathogen Porphyromonas gingivalis.
  Int J Mol Sci, 11, 3252-3265.  
20628577 M.Egerer, and K.J.Satchell (2010).
Inositol hexakisphosphate-induced autoprocessing of large bacterial protein toxins.
  PLoS Pathog, 6, e1000942.  
19465933 A.Shen, P.J.Lupardus, V.E.Albrow, A.Guzzetta, J.C.Powers, K.C.Garcia, and M.Bogyo (2009).
Mechanistic and structural insights into the proteolytic activation of Vibrio cholerae MARTX toxin.
  Nat Chem Biol, 5, 469-478.
PDB code: 3gcd
19620709 K.Prochazkova, L.A.Shuvalova, G.Minasov, Z.Voburka, W.F.Anderson, and K.J.Satchell (2009).
Structural and molecular mechanism for autoprocessing of MARTX toxin of Vibrio cholerae at multiple sites.
  J Biol Chem, 284, 26557-26568.
PDB code: 3fzy
19688822 M.Shokhen, N.Khazanov, and A.Albeck (2009).
Challenging a paradigm: theoretical calculations of the protonation state of the Cys25-His159 catalytic diad in free papain.
  Proteins, 77, 916-926.  
19416015 R.E.Fitzpatrick, L.C.Wijeyewickrema, and R.N.Pike (2009).
The gingipains: scissors and glue of the periodontal pathogen, Porphyromonas gingivalis.
  Future Microbiol, 4, 471-487.  
18294123 G.N.Rudenskaya, and D.V.Pupov (2008).
Cysteine proteinases of microorganisms and viruses.
  Biochemistry (Mosc), 73, 1.  
18845756 P.J.Lupardus, A.Shen, M.Bogyo, and K.C.Garcia (2008).
Small molecule-induced allosteric activation of the Vibrio cholerae RTX cysteine protease domain.
  Science, 322, 265-268.
PDB code: 3eeb
17967946 D.Vercammen, W.Declercq, P.Vandenabeele, and F.Van Breusegem (2007).
Are metacaspases caspases?
  J Cell Biol, 179, 375-380.  
17142394 K.A.Nguyen, J.Travis, and J.Potempa (2007).
Does the importance of the C-terminal residues in the maturation of RgpB from Porphyromonas gingivalis reveal a novel mechanism for protein export in a subgroup of Gram-Negative bacteria?
  J Bacteriol, 189, 833-843.  
16923905 C.A.Seers, N.Slakeski, P.D.Veith, T.Nikolof, Y.Y.Chen, S.G.Dashper, and E.C.Reynolds (2006).
The RgpB C-terminal domain has a role in attachment of RgpB to the outer membrane and belongs to a novel C-terminal-domain family found in Porphyromonas gingivalis.
  J Bacteriol, 188, 6376-6386.  
16988242 S.M.Sheets, J.Potempa, J.Travis, H.M.Fletcher, and C.A.Casiano (2006).
Gingipains from Porphyromonas gingivalis W83 synergistically disrupt endothelial cell adhesion and can induce caspase-independent apoptosis.
  Infect Immun, 74, 5667-5678.  
16524480 S.Urnowey, T.Ansai, V.Bitko, K.Nakayama, T.Takehara, and S.Barik (2006).
Temporal activation of anti- and pro-apoptotic factors in human gingival fibroblasts infected with the periodontal pathogen, Porphyromonas gingivalis: potential role of bacterial proteases in host signalling.
  BMC Microbiol, 6, 26.  
15548596 C.J.Webb, S.Lakhe-Reddy, C.M.Romfo, and J.A.Wise (2005).
Analysis of mutant phenotypes and splicing defects demonstrates functional collaboration between the large and small subunits of the essential splicing factor U2AF in vivo.
  Mol Biol Cell, 16, 584-596.  
16200200 I.N.Lavrik, A.Golks, and P.H.Krammer (2005).
Caspases: pharmacological manipulation of cell death.
  J Clin Invest, 115, 2665-2672.  
15678420 M.Groll, M.Bochtler, H.Brandstetter, T.Clausen, and R.Huber (2005).
Molecular machines for protein degradation.
  Chembiochem, 6, 222-256.  
16041000 M.Rangarajan, A.Hashim, J.Aduse-Opoku, N.Paramonov, E.F.Hounsell, and M.A.Curtis (2005).
Expression of Arg-Gingipain RgpB is required for correct glycosylation and stability of monomeric Arg-gingipain RgpA from Porphyromonas gingivalis W50.
  Infect Immun, 73, 4864-4878.  
15652979 T.Olczak, W.Simpson, X.Liu, and C.A.Genco (2005).
Iron and heme utilization in Porphyromonas gingivalis.
  FEMS Microbiol Rev, 29, 119-144.  
15121844 C.J.Webb, and J.A.Wise (2004).
The splicing factor U2AF small subunit is functionally conserved between fission yeast and humans.
  Mol Cell Biol, 24, 4229-4240.  
15326173 D.Vercammen, B.van de Cotte, G.De Jaeger, D.Eeckhout, P.Casteels, K.Vandepoele, I.Vandenberghe, J.Van Beeumen, D.Inzé, and F.Van Breusegem (2004).
Type II metacaspases Atmc4 and Atmc9 of Arabidopsis thaliana cleave substrates after arginine and lysine.
  J Biol Chem, 279, 45329-45336.  
15297553 M.A.Nadkarni, K.A.Nguyen, C.C.Chapple, A.A.DeCarlo, N.A.Jacques, and N.Hunter (2004).
Distribution of Porphyromonas gingivalis biotypes defined by alleles of the kgp (Lys-gingipain) gene.
  J Clin Microbiol, 42, 3873-3876.  
15554977 M.Sztukowska, A.Sroka, M.Bugno, A.Banbula, Y.Takahashi, R.N.Pike, C.A.Genco, J.Travis, and J.Potempa (2004).
The C-terminal domains of the gingipain K polyprotein are necessary for assembly of the active enzyme and expression of associated activities.
  Mol Microbiol, 54, 1393-1408.  
15009210 N.E.Labrou, and D.J.Rigden (2004).
The structure-function relationship in the clostripain family of peptidases.
  Eur J Biochem, 271, 983-992.  
12655644 B.Eisenhaber, S.Maurer-Stroh, M.Novatchkova, G.Schneider, and F.Eisenhaber (2003).
Enzymes and auxiliary factors for GPI lipid anchor biosynthesis and post-translational transfer to proteins.
  Bioessays, 25, 367-385.  
14501113 J.Koepke, E.I.Scharff, C.Lücke, H.Rüterjans, and G.Fritzsch (2003).
Statistical analysis of crystallographic data obtained from squid ganglion DFPase at 0.85 A resolution.
  Acta Crystallogr D Biol Crystallogr, 59, 1744-1754.
PDB code: 1pjx
12533545 J.Mikolajczyk, K.M.Boatright, H.R.Stennicke, T.Nazif, J.Potempa, M.Bogyo, and G.S.Salvesen (2003).
Sequential autolytic processing activates the zymogen of Arg-gingipain.
  J Biol Chem, 278, 10458-10464.  
12593605 T.Imamura (2003).
The role of gingipains in the pathogenesis of periodontal disease.
  J Periodontol, 74, 111-118.  
12111749 C.T.Supuran, A.Scozzafava, and B.W.Clare (2002).
Bacterial protease inhibitors.
  Med Res Rev, 22, 329-372.  
12228316 E.Hintermann, S.K.Haake, U.Christen, A.Sharabi, and V.Quaranta (2002).
Discrete proteolysis of focal contact and adherens junction components in Porphyromonas gingivalis-infected oral keratinocytes: a strategy for cell adhesion and migration disabling.
  Infect Immun, 70, 5846-5856.  
12437101 H.Brandstetter, J.S.Kim, M.Groll, P.Göttig, and R.Huber (2002).
Structural basis for the processive protein degradation by tricorn protease.
  Biol Chem, 383, 1157-1165.  
12437105 J.A.Krauser, J.Potempa, J.Travis, and J.C.Powers (2002).
Inhibition of arginine gingipains (RgpB and HRgpA) with benzamidine inhibitors: zinc increases inhibitory potency.
  Biol Chem, 383, 1193-1198.  
11835511 L.Aravind, and E.V.Koonin (2002).
Classification of the caspase-hemoglobinase fold: detection of new families and implications for the origin of the eukaryotic separins.
  Proteins, 46, 355-367.  
11688723 A.Banbula, P.Mak, M.Smoluch, J.Travis, and J.Potempa (2001).
Arginine-specific cysteine proteinase from porphyromonas gingivalis as a convenient tool in protein chemistry.
  Biol Chem, 382, 1399-1404.  
11517925 A.J.Barrett, and N.D.Rawlings (2001).
Evolutionary lines of cysteine peptidases.
  Biol Chem, 382, 727-733.  
11700297 K.Nasmyth (2001).
Disseminating the genome: joining, resolving, and separating sister chromatids during mitosis and meiosis.
  Annu Rev Genet, 35, 673-745.  
11292714 M.Kuboniwa, A.Amano, S.Shizukuishi, I.Nakagawa, and S.Hamada (2001).
Specific antibodies to Porphyromonas gingivalis Lys-gingipain by DNA vaccination inhibit bacterial binding to hemoglobin and protect mice from infection.
  Infect Immun, 69, 2972-2979.  
11401991 M.Oido-Mori, R.Rezzonico, P.L.Wang, Y.Kowashi, J.M.Dayer, P.C.Baehni, and C.Chizzolini (2001).
Porphyromonas gingivalis gingipain-R enhances interleukin-8 but decreases gamma interferon-inducible protein 10 production by human gingival fibroblasts in response to T-cell contact.
  Infect Immun, 69, 4493-4501.  
11752425 S.J.Riedl, P.Fuentes-Prior, M.Renatus, N.Kairies, S.Krapp, R.Huber, G.S.Salvesen, and W.Bode (2001).
Structural basis for the activation of human procaspase-7.
  Proc Natl Acad Sci U S A, 98, 14790-14795.
PDB code: 1gqf
11557483 T.Imamura, K.Matsushita, J.Travis, and J.Potempa (2001).
Inhibition of trypsin-like cysteine proteinases (gingipains) from Porphyromonas gingivalis by tetracycline and its analogues.
  Antimicrob Agents Chemother, 45, 2871-2876.  
  11090634 A.G.Uren, K.O'Rourke, L.A.Aravind, M.T.Pisabarro, S.Seshagiri, E.V.Koonin, and V.M.Dixit (2000).
Identification of paracaspases and metacaspases: two ancient families of caspase-like proteins, one of which plays a key role in MALT lymphoma.
  Mol Cell, 6, 961-967.  
11209755 E.Estébanez-Perpiña, P.Fuentes-Prior, D.Belorgey, M.Braun, R.Kiefersauer, K.Maskos, R.Huber, H.Rubin, and W.Bode (2000).
Crystal structure of the caspase activator human granzyme B, a proteinase highly specific for an Asp-P1 residue.
  Biol Chem, 381, 1203-1214.
PDB code: 1fq3
11081625 F.Uhlmann, D.Wernic, M.A.Poupart, E.V.Koonin, and K.Nasmyth (2000).
Cleavage of cohesin by the CD clan protease separin triggers anaphase in yeast.
  Cell, 103, 375-386.  
11114501 M.G.Grütter (2000).
Caspases: key players in programmed cell death.
  Curr Opin Struct Biol, 10, 649-655.  
11154429 R.J.Lamont, and H.F.Jenkinson (2000).
Subgingival colonization by Porphyromonas gingivalis.
  Oral Microbiol Immunol, 15, 341-349.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.