PDBsum entry: 2q3z

Transferase

PDB id: 2q3z

Contents

Protein chain

655 a.a. *

Ligands

ACE-PRO-ONL-LEU-PRO-PHE-NH2

SO4 ×5

Waters ×262

* Residue conservation analysis

PDB id:

2q3z

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.

Resolution:

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

Date:

30-May-07 Release date: 23-Oct-07

Protein chain

P21980  (TGM2_HUMAN) -  Protein-glutamine gamma-glutamyltransferase 2

Seq: 687 a.a.

Struc: 655 a.a.*

* PDB and UniProt seqs differ at 5 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.2.3.2.13 - Protein-glutamine gamma-glutamyltransferase.
• 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: Calcium

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

 Gene Ontology (GO) functional annotation 

• Cellular component: plasma membrane (3 terms)
• Biological process: metabolic process (15 terms)
• Biochemical function: protein binding (7 terms)

reference

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.

ABSTRACT

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.