3PB6

Crystal structure of the catalytic domain of human Golgi-resident glutaminyl cyclase at pH 6.5

Summary for 3PB6

• Entry DOI: 10.2210/pdb3pb6/pdb
• Related: 3PB4 3PB7 3PB8 3PB9 3PBB 3PBE
• Descriptor: Glutaminyl-peptide cyclotransferase-like protein, CACODYLATE ION, ZINC ION, ... (4 entities in total)
• Functional Keywords: alpha/beta protein, alpha/beta-mixed fold, glutaminyl cyclase, golgi membrane, transferase
• Biological source: Homo sapiens (human)
• Cellular location: Golgi apparatus membrane; Single-pass type I membrane protein: Q9NXS2
• Total number of polymer chains: 1
• Total formula weight: 37271.13

Authors

Huang, K.F.,Liaw, S.S.,Huang, W.L.,Chia, C.Y.,Lo, Y.C.,Chen, Y.L.,Wang, A.H.J. (deposition date: 2010-10-20, release date: 2011-02-02, Last modification date: 2023-11-01)

Primary citation

Huang, K.F.,Liaw, S.S.,Huang, W.L.,Chia, C.Y.,Lo, Y.C.,Chen, Y.L.,Wang, A.H.J.
Structures of human Golgi-resident glutaminyl cyclase and its complexes with inhibitors reveal a large loop movement upon inhibitor binding
J.Biol.Chem., 286:12439-12449, 2011

PubMed Abstract: Aberrant pyroglutamate formation at the N terminus of certain peptides and proteins, catalyzed by glutaminyl cyclases (QCs), is linked to some pathological conditions, such as Alzheimer disease. Recently, a glutaminyl cyclase (QC) inhibitor, PBD150, was shown to be able to reduce the deposition of pyroglutamate-modified amyloid-β peptides in brain of transgenic mouse models of Alzheimer disease, leading to a significant improvement of learning and memory in those transgenic animals. Here, we report the 1.05-1.40 Å resolution structures, solved by the sulfur single-wavelength anomalous dispersion phasing method, of the Golgi-luminal catalytic domain of the recently identified Golgi-resident QC (gQC) and its complex with PBD150. We also describe the high-resolution structures of secretory QC (sQC)-PBD150 complex and two other gQC-inhibitor complexes. gQC structure has a scaffold similar to that of sQC but with a relatively wider and negatively charged active site, suggesting a distinct substrate specificity from sQC. Upon binding to PBD150, a large loop movement in gQC allows the inhibitor to be tightly held in its active site primarily by hydrophobic interactions. Further comparisons of the inhibitor-bound structures revealed distinct interactions of the inhibitors with gQC and sQC, which are consistent with the results from our inhibitor assays reported here. Because gQC and sQC may play different biological roles in vivo, the different inhibitor binding modes allow the design of specific inhibitors toward gQC and sQC.

PubMed: 21288892
DOI: 10.1074/jbc.M110.208595

Experimental method

X-RAY DIFFRACTION (1.05 Å)