PDBsum entry 2afx

Transferase

PDB id: 2afx

Contents

Protein chain

323 a.a. *

Ligands

SO4 ×2

1BN ×2

Metals

_ZN ×2

Waters ×591

* Residue conservation analysis

PDB id:

2afx

Name:

Transferase

Title:

Crystal structure of human glutaminyl cyclase in complex with 1- benzylimidazole

Structure:

Glutaminyl-peptide cyclotransferase. Chain: a, b. Fragment: residues 33-361. Synonym: qc, glutaminyl-tRNA cyclotransferase, glutaminyl cyclase. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: qpct. Expressed in: escherichia coli. Expression_system_taxid: 469008.

Biol. unit:

Hexamer (from PQS)

Resolution:

1.64Å R-factor: 0.177 R-free: 0.205

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

Date:

26-Jul-05 Release date: 23-Aug-05

Protein chains

Q16769  (QPCT_HUMAN) -  Glutaminyl-peptide cyclotransferase from Homo sapiens

Seq: 361 a.a.

Struc: 323 a.a.

Enzyme reactions

• Enzyme class: E.C.2.3.2.5 - glutaminyl-peptide cyclotransferase.
• Reaction: N-terminal L-glutaminyl-[peptide] = N-terminal 5-oxo-L-prolyl-[peptide] + NH4⁺

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

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.

ABSTRACT

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.