2AFU

Crystal structure of human glutaminyl cyclase in complex with glutamine t-butyl ester

Summary for 2AFU

• Entry DOI: 10.2210/pdb2afu/pdb
• Related: 2AFO 2AFS 2AFW 2AFX 2AFZ
• Descriptor: Glutaminyl-peptide cyclotransferase, ZINC ION, TERT-BUTYL D-ALPHA-GLUTAMINATE, ... (4 entities in total)
• Functional Keywords: alpha-beta protein, metalloprotein, transferase
• Biological source: Homo sapiens (human)
• Cellular location: Secreted: Q16769
• Total number of polymer chains: 2
• Total formula weight: 75648.15

Authors

Huang, K.F.,Liu, Y.L.,Cheng, W.J.,Ko, T.P.,Wang, A.H.J. (deposition date: 2005-07-26, release date: 2005-08-23, Last modification date: 2024-05-29)

Primary citation

Huang, K.F.,Liu, Y.L.,Cheng, W.J.,Ko, T.P.,Wang, A.H.
Crystal structures of human glutaminyl cyclase, an enzyme responsible for protein N-terminal pyroglutamate formation
Proc.Natl.Acad.Sci.Usa, 102:13117-13122, 2005

PubMed 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.

PubMed: 16135565
DOI: 10.1073/pnas.0504184102

Experimental method

X-RAY DIFFRACTION (2.22 Å)