PDBsum entry 2q3z

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protein ligands links
Transferase PDB id
Protein chain
655 a.a. *
SO4 ×5
Waters ×262
* Residue conservation analysis
PDB id:
Name: Transferase
Title: Transglutaminase 2 undergoes large conformational change upo activation
Structure: Transglutaminase 2. Chain: a. Synonym: tissue transglutaminase, tgasE C, tgc, tgc, transglutaminase-2, tgase- h. Engineered: yes. Polypeptide. Chain: x. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: tgm2. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes. Other_details: chemically synthesized.
2.00Å     R-factor:   0.231     R-free:   0.266
Authors: P.Strop,D.M.Pinkas,A.T.Brunger,C.Khosla
Key ref:
D.M.Pinkas et al. (2007). Transglutaminase 2 undergoes a large conformational change upon activation. PLoS Biol, 5, e327. PubMed id: 18092889 DOI: 10.1371/journal.pbio.0050327
30-May-07     Release date:   23-Oct-07    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P21980  (TGM2_HUMAN) -  Protein-glutamine gamma-glutamyltransferase 2
687 a.a.
655 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 5 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: E.C.  - Protein-glutamine gamma-glutamyltransferase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Protein glutamine + alkylamine = protein N5-alkylglutamine + NH3
Protein glutamine
Bound ligand (Het Group name = ONL)
matches with 53.33% similarity
+ alkylamine
= protein N(5)-alkylglutamine
+ NH(3)
      Cofactor: Ca(2+)
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     plasma membrane   6 terms 
  Biological process     positive regulation of cell adhesion   16 terms 
  Biochemical function     protein binding     7 terms  


DOI no: 10.1371/journal.pbio.0050327 PLoS Biol 5:e327 (2007)
PubMed id: 18092889  
Transglutaminase 2 undergoes a large conformational change upon activation.
D.M.Pinkas, P.Strop, A.T.Brunger, C.Khosla.
Human transglutaminase 2 (TG2), a member of a large family of enzymes that catalyze protein crosslinking, plays an important role in the extracellular matrix biology of many tissues and is implicated in the gluten-induced pathogenesis of celiac sprue. Although vertebrate transglutaminases have been studied extensively, thus far all structurally characterized members of this family have been crystallized in conformations with inaccessible active sites. We have trapped human TG2 in complex with an inhibitor that mimics inflammatory gluten peptide substrates and have solved, at 2-A resolution, its x-ray crystal structure. The inhibitor stabilizes TG2 in an extended conformation that is dramatically different from earlier transglutaminase structures. The active site is exposed, revealing that catalysis takes place in a tunnel, bridged by two tryptophan residues that separate acyl-donor from acyl-acceptor and stabilize the tetrahedral reaction intermediates. Site-directed mutagenesis was used to investigate the acyl-acceptor side of the tunnel, yielding mutants with a marked increase in preference for hydrolysis over transamidation. By providing the ability to visualize this activated conformer, our results create a foundation for understanding the catalytic as well as the non-catalytic roles of TG2 in biology, and for dissecting the process by which the autoantibody response to TG2 is induced in celiac sprue patients.
  Selected figure(s)  
Figure 4.
Figure 4.The Active Site of TG2 and Enzyme–Inhibitor Interactions
(A) Electrostatic potential surface of TG2 (red indicates negative charge; blue, positive; contoured at −15 k[B]T to +15 k[B]T) in the vicinity of the peptide inhibitor. (Carbon is indicated by cyan; nitrogen by blue; and oxygen by red.)
(B) Surface representation of the active-site tryptophan bridge. W332, W241, and inhibitor are shown in green, red, and cyan, respectively. The proposed acyl-acceptor approach site is indicated.
(C) Stereo representation of the active site of TG2. The backbone of TG2 is shown as ribbons. The bridge tryptophans and a T360 that resides in front of the proposed acyl-acceptor entrance are shown as sticks with semitransparent surfaces. It can be seen that the bridging tryptophan residues reside on separate loops above the catalytic Cys (sulfur is indicated by yellow). The thioether attachment of the inhibitor (cyan indicates inhibitor carbons, and gray indicates TG2 carbons) is also evident.
(D) Hydrogen-bonding interactions between TG2 and the peptide are shown as dashed lines.
(E) Schematic diagram of hydrophobic interactions between TG2 and the inhibitor.
Figure 5.
Figure 5.σ[A] Weighted Electron Density Maps (2Fo-Fc) Contoured at 1σ in the Vicinity of Cys-370 and Cys-371
(A) In the GDP-bound structure [16], Cys-370 and Cys-371 are reduced. (B) In the inhibitor-bound structure, the cysteine residues form a vicinal disulfide bond, causing the intervening peptide bind to take on a cis configuration.
  The above figures are reprinted from an Open Access publication published by Public Library of Science: PLoS Biol (2007, 5, e327) copyright 2007.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21215619 C.Klöck, X.Jin, K.Choi, C.Khosla, P.B.Madrid, A.Spencer, B.C.Raimundo, P.Boardman, G.Lanza, and J.H.Griffin (2011).
Acylideneoxoindoles: a new class of reversible inhibitors of human transglutaminase 2.
  Bioorg Med Chem Lett, 21, 2692-2696.  
21304968 G.Colak, J.W.Keillor, and G.V.Johnson (2011).
Cytosolic guanine nucledotide binding deficient form of transglutaminase 2 (R580a) potentiates cell death in oxygen glucose deprivation.
  PLoS One, 6, e16665.  
21283799 H.F.Al-Jallad, V.D.Myneni, S.A.Piercy-Kotb, N.Chabot, A.Mulani, J.W.Keillor, and M.T.Kaartinen (2011).
Plasma membrane factor XIIIA transglutaminase activity regulates osteoblast matrix secretion and deposition by affecting microtubule dynamics.
  PLoS One, 6, e15893.  
20831445 I.Azimi, J.W.Wong, and P.J.Hogg (2011).
Control of mature protein function by allosteric disulfide bonds.
  Antioxid Redox Signal, 14, 113-126.  
20880254 I.Komáromi, Z.Bagoly, and L.Muszbek (2011).
Factor XIII: novel structural and functional aspects.
  J Thromb Haemost, 9, 9.  
21276939 L.Dafik, and C.Khosla (2011).
Dihydroisoxazole analogs for labeling and visualization of catalytically active transglutaminase 2.
  Chem Biol, 18, 58-66.  
21317917 R.Uibo, M.Panarina, K.Teesalu, I.Talja, E.Sepp, M.Utt, M.Mikelsaar, K.Heilman, O.Uibo, and T.Vorobjova (2011).
Celiac disease in patients with type 1 diabetes: a condition with distinct changes in intestinal immunity?
  Cell Mol Immunol, 8, 150-156.  
21310073 S.J.Yi, J.Groffen, and N.Heisterkamp (2011).
Bcr is a substrate for Transglutaminase 2 cross-linking activity.
  BMC Biochem, 12, 8.  
20156196 C.Faye, A.Inforzato, M.Bignon, D.J.Hartmann, L.Muller, L.Ballut, B.R.Olsen, A.J.Day, and S.Ricard-Blum (2010).
Transglutaminase-2: a new endostatin partner in the extracellular matrix of endothelial cells.
  Biochem J, 427, 467-475.  
20033238 C.M.Bergamini, A.Dondi, V.Lanzara, M.Squerzanti, C.Cervellati, K.Montin, C.Mischiati, G.Tasco, R.Collighan, M.Griffin, and R.Casadio (2010).
Thermodynamics of binding of regulatory ligands to tissue transglutaminase.
  Amino Acids, 39, 297-304.  
20148342 D.Park, S.S.Choi, and K.S.Ha (2010).
Transglutaminase 2: a multi-functional protein in multiple subcellular compartments.
  Amino Acids, 39, 619-631.  
21035737 N.Chabot, S.Moreau, A.Mulani, P.Moreau, and J.W.Keillor (2010).
Fluorescent probes of tissue transglutaminase reveal its association with arterial stiffening.
  Chem Biol, 17, 1143-1150.  
20964734 P.G.Mastroberardino, and M.Piacentini (2010).
Type 2 transglutaminase in Huntington's disease: a double-edged sword with clinical potential.
  J Intern Med, 268, 419-431.  
20144949 R.Di Niro, A.M.Sulic, F.Mignone, S.D'Angelo, R.Bordoni, M.Iacono, R.Marzari, T.Gaiotto, M.Lavric, A.R.Bradbury, L.Biancone, D.Zevin-Sonkin, G.De Bellis, C.Santoro, and D.Sblattero (2010).
Rapid interactome profiling by massive sequencing.
  Nucleic Acids Res, 38, e110.  
20300628 S.Boscolo, A.Lorenzon, D.Sblattero, F.Florian, M.Stebel, R.Marzari, T.Not, D.Aeschlimann, A.Ventura, M.Hadjivassiliou, and E.Tongiorgi (2010).
Anti transglutaminase antibodies cause ataxia in mice.
  PLoS One, 5, e9698.  
19998405 T.S.Lai, C.Davies, and C.S.Greenberg (2010).
Human tissue transglutaminase is inhibited by pharmacologic and chemical acetylation.
  Protein Sci, 19, 229-235.  
19680746 E.Myrsky, S.Caja, Z.Simon-Vecsei, I.R.Korponay-Szabo, C.Nadalutti, R.Collighan, A.Mongeot, M.Griffin, M.Mäki, K.Kaukinen, and K.Lindfors (2009).
Celiac disease IgA modulates vascular permeability in vitro through the activity of transglutaminase 2 and RhoA.
  Cell Mol Life Sci, 66, 3375-3385.  
19443237 G.A.Heap, and D.A.van Heel (2009).
Genetics and pathogenesis of coeliac disease.
  Semin Immunol, 21, 346-354.  
18600381 I.Caputo, M.V.Barone, S.Martucciello, M.Lepretti, and C.Esposito (2009).
Tissue transglutaminase in celiac disease: role of autoantibodies.
  Amino Acids, 36, 693-699.  
18594945 K.Lindfors, K.Kaukinen, and M.Mäki (2009).
A role for anti-transglutaminase 2 autoantibodies in the pathogenesis of coeliac disease?
  Amino Acids, 36, 685-691.  
19568436 S.Gundemir, and G.V.Johnson (2009).
Intracellular localization and conformational state of transglutaminase 2: implications for cell death.
  PLoS One, 4, e6123.  
19840940 S.J.Yi, J.Groffen, and N.Heisterkamp (2009).
Transglutaminase 2 regulates the GTPase-activating activity of Bcr.
  J Biol Chem, 284, 35645-35651.  
19342211 S.W.Qiao, L.M.Sollid, and R.S.Blumberg (2009).
Antigen presentation in celiac disease.
  Curr Opin Immunol, 21, 111-117.  
20161049 T.M.Jeitner, N.A.Muma, K.P.Battaile, and A.J.Cooper (2009).
Transglutaminase activation in neurodegenerative diseases.
  Future Neurol, 4, 449-467.  
18373732 V.Villanacci, T.Not, D.Sblattero, T.Gaiotto, F.Chirdo, A.Galletti, and G.Bassotti (2009).
Mucosal tissue transglutaminase expression in celiac disease.
  J Cell Mol Med, 13, 334-340.  
18793760 J.Stamnaes, B.Fleckenstein, and L.M.Sollid (2008).
The propensity for deamidation and transamidation of peptides by transglutaminase 2 is dependent on substrate affinity and reaction conditions.
  Biochim Biophys Acta, 1784, 1804-1811.  
18825674 M.Hadjivassiliou, P.Aeschlimann, A.Strigun, D.S.Sanders, N.Woodroofe, and D.Aeschlimann (2008).
Autoantibodies in gluten ataxia recognize a novel neuronal transglutaminase.
  Ann Neurol, 64, 332-343.  
18365016 M.Siegel, P.Strnad, R.E.Watts, K.Choi, B.Jabri, M.B.Omary, and C.Khosla (2008).
Extracellular transglutaminase 2 is catalytically inactive, but is transiently activated upon tissue injury.
  PLoS ONE, 3, e1861.  
18365012 M.T.Bethune, E.Ribka, C.Khosla, and K.Sestak (2008).
Transepithelial transport and enzymatic detoxification of gluten in gluten-sensitive rhesus macaques.
  PLoS ONE, 3, e1857.  
  19079660 Q.Ruan, J.Tucholski, S.Gundemir, and G.V.Johnson Voll (2008).
The Differential Effects of R580A Mutation on Transamidation and GTP Binding Activity of Rat and Human Type 2 Transglutaminase.
  Int J Clin Exp Med, 1, 248-259.  
18804034 T.S.Lai, Y.Liu, T.Tucker, K.R.Daniel, D.C.Sane, E.Toone, J.R.Burke, W.J.Strittmatter, and C.S.Greenberg (2008).
Identification of chemical inhibitors to human tissue transglutaminase by screening existing drug libraries.
  Chem Biol, 15, 969-978.  
18162046 F.Koning (2007).
A tertiary twist to the transglutaminase tale.
  PLoS Biol, 5, e337.  
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.