PDBsum entry 2afu

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protein ligands metals Protein-protein interface(s) links
Transferase PDB id
Protein chain
321 a.a. *
BGT ×2
_ZN ×2
Waters ×511
* Residue conservation analysis
PDB id:
Name: Transferase
Title: Crystal structure of human glutaminyl cyclase in complex wit glutamine t-butyl ester
Structure: Glutaminyl-peptide cyclotransferase. Chain: a, b. Fragment: residues 33-361. Synonym: qc, glutaminyl-tRNA cyclotransferase, glutaminyl c engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: qpct. Expressed in: escherichia coli. Expression_system_taxid: 469008.
Biol. unit: Hexamer (from PQS)
2.22Å     R-factor:   0.188     R-free:   0.226
Authors: K.F.Huang,Y.L.Liu,W.J.Cheng,T.P.Ko,A.H.J.Wang
Key ref:
K.F.Huang et al. (2005). Crystal structures of human glutaminyl cyclase, an enzyme responsible for protein N-terminal pyroglutamate formation. Proc Natl Acad Sci U S A, 102, 13117-13122. PubMed id: 16135565 DOI: 10.1073/pnas.0504184102
26-Jul-05     Release date:   23-Aug-05    
Go to PROCHECK summary

Protein chains
Pfam   ArchSchema ?
Q16769  (QPCT_HUMAN) -  Glutaminyl-peptide cyclotransferase
361 a.a.
321 a.a.*
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Enzyme reactions 
   Enzyme class: E.C.  - Glutaminyl-peptide cyclotransferase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: L-glutaminyl-peptide = 5-oxoprolyl-peptide + NH3
Bound ligand (Het Group name = BGT)
matches with 45.00% similarity
= 5-oxoprolyl-peptide
+ NH(3)
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     extracellular region   2 terms 
  Biological process     cellular protein modification process   2 terms 
  Biochemical function     transferase activity     5 terms  


    Added reference    
DOI no: 10.1073/pnas.0504184102 Proc Natl Acad Sci U S A 102:13117-13122 (2005)
PubMed id: 16135565  
Crystal structures of human glutaminyl cyclase, an enzyme responsible for protein N-terminal pyroglutamate formation.
K.F.Huang, Y.L.Liu, W.J.Cheng, T.P.Ko, A.H.Wang.
N-terminal pyroglutamate (pGlu) formation from its glutaminyl (or glutamyl) precursor is required in the maturation of numerous bioactive peptides. The aberrant formation of pGlu may be related to several pathological processes, such as osteoporosis and amyloidotic diseases. This N-terminal cyclization reaction, once thought to proceed spontaneously, is greatly facilitated by the enzyme glutaminyl cyclase (QC). To probe this important but poorly understood modification, we present here the structure of human QC in free form and bound to a substrate and three imidazole-derived inhibitors. The structure reveals an alpha/beta scaffold akin to that of two-zinc exopeptidases but with several insertions and deletions, particularly in the active-site region. The relatively closed active site displays alternate conformations due to the different indole orientations of Trp-207, resulting in two substrate (glutamine t-butyl ester)-binding modes. The single zinc ion in the active site is coordinated to three conserved residues and one water molecule, which is replaced by an imidazole nitrogen upon binding of the inhibitors. Together with structural and kinetic analyses of several active-site-mutant enzymes, a catalysis mechanism of the formation of protein N-terminal pGlu is proposed. Our results provide a structural basis for the rational design of inhibitors against QC-associated disorders.
  Selected figure(s)  
Figure 1.
Fig. 1. Structure of human QC. (A) A ribbon diagram of the overall structure of human QC. The central six -strands are colored orange. The -helices located on the top, bottom, and edge are colored cyan, magenta, and yellow, respectively. The zinc ion is shown as a yellow sphere. The zinc-coordinated residues, Arg-54 (genetic mutation to Trp residue occurred frequently in adult women with osteoporosis), and a sulfate ion are depicted with a ball-and-stick model. The coils and loops adjacent to the catalytic center are painted green, whereas those distant from the active site are colored gray. Gray dots represent the disordered region of residues 183-188. (B) A topology diagram of the human QC structure. The color codes for secondary structural elements are identical to those in A.(C) A stereoview of the human QC catalytic region. The active-site residues in conf-A are shown and labeled. Possible hydrogen and coordination bonds are represented with dotted lines colored cyan and yellow, respectively. The green dotted lines depict the possibly unusual hydrogen bonds between D305 and E201 (3.06 Å) and between D305 and D248 (2.53 Å).
Figure 4.
Fig. 4. Structures of human QC bound to imidazole-derived inhibitors. (A) The zinc-binding environment of the free-form human QC. The 2F[o] - F[c] electron density maps (contoured at 1.0 ) (gray) corresponding to the water molecules inside the active-site pocket are shown. Representations of the models, hydrogen bonds, and coordination bonds are identical to those in Fig. 1C. (B-D) Structures of human QC bound to 1-vinylimidazole (1.68-Å resolution), 1-benzylimidazole (1.64-Å resolution), and N- -acetylhistamine (1.56-Å resolution), respectively. The 2F[o] - F[c] maps (contoured at 1.0 ) (magenta) for the inhibitors are overlaid with the final refined models. Distances for enzyme-inhibitor interaction are indicated in Å.
  Figures were selected by the author.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20110353 A.J.Oakley, M.Coggan, and P.G.Board (2010).
Identification and characterization of gamma-glutamylamine cyclotransferase, an enzyme responsible for gamma-glutamyl-epsilon-lysine catabolism.
  J Biol Chem, 285, 9642-9648.
PDB codes: 3jub 3juc 3jud
20868223 D.R.Carrillo, C.Parthier, N.Jänckel, J.Grandke, M.Stelter, S.Schilling, M.Boehme, P.Neumann, R.Wolf, H.U.Demuth, M.T.Stubbs, and J.U.Rahfeld (2010).
Kinetic and structural characterization of bacterial glutaminyl cyclases from Zymomonas mobilis and Myxococcus xanthus.
  Biol Chem, 391, 1419-1428.
PDB codes: 3nok 3nol 3nom
19670211 R.Koike, A.Kidera, and M.Ota (2009).
Alteration of oligomeric state and domain architecture is essential for functional transformation between transferase and hydrolase with the same scaffold.
  Protein Sci, 18, 2060-2066.  
18470930 M.Calvaresi, M.Garavelli, and A.Bottoni (2008).
Computational evidence for the catalytic mechanism of glutaminyl cyclase. A DFT investigation.
  Proteins, 73, 527-538.  
18979624 S.Schilling, C.Wasternack, and H.U.Demuth (2008).
Glutaminyl cyclases from animals and plants: a case of functionally convergent protein evolution.
  Biol Chem, 389, 983-991.  
17576216 J.L.Pereira, E.F.Noronha, R.N.Miller, and O.L.Franco (2007).
Novel insights in the use of hydrolytic enzymes secreted by fungi with biotechnological potential.
  Lett Appl Microbiol, 44, 573-581.  
17576082 K.Tessmar-Raible (2007).
The evolution of neurosecretory centers in bilaterian forebrains: insights from protostomes.
  Semin Cell Dev Biol, 18, 492-501.  
17261077 S.Schilling, I.Stenzel, A.von Bohlen, M.Wermann, K.Schulz, H.U.Demuth, and C.Wasternack (2007).
Isolation and characterization of the glutaminyl cyclases from Solanum tuberosum and Arabidopsis thaliana: implications for physiological functions.
  Biol Chem, 388, 145-153.  
17081122 T.Guevara, N.Mallorquí-Fernández, R.García-Castellanos, S.García-Piqué, G.Ebert Petersen, C.Lauritzen, J.Pedersen, J.Arnau, F.X.Gomis-Rüth, and M.Solà (2006).
Papaya glutamine cyclotransferase shows a singular five-fold beta-propeller architecture that suggests a novel reaction mechanism.
  Biol Chem, 387, 1479-1486.
PDB code: 2iwa
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