4YWY

Crystal Structure of double mutant Y115E Y117E human Glutaminyl Cyclase in complex with inhibitor PBD-150

Summary for 4YWY

• Entry DOI: 10.2210/pdb4ywy/pdb
• Descriptor: Glutaminyl-peptide cyclotransferase, ZINC ION, 1-(3,4-dimethoxyphenyl)-3-[3-(1H-imidazol-1-yl)propyl]thiourea, ... (7 entities in total)
• Functional Keywords: alzheimer disease, cyclotransferase soluble variant, pbd-150 inhibitor, transferase
• Biological source: Homo sapiens (Human)
• Cellular location: Secreted : Q16769
• Total number of polymer chains: 3
• Total formula weight: 125483.44

Authors

Di Pisa, F.,Pozzi, C.,Benvenuti, M.,Mangani, S. (deposition date: 2015-03-21, release date: 2015-08-05, Last modification date: 2024-01-10)

Primary citation

DiPisa, F.,Pozzi, C.,Benvenuti, M.,Andreini, M.,Marconi, G.,Mangani, S.
The soluble Y115E-Y117E variant of human glutaminyl cyclase is a valid target for X-ray and NMR screening of inhibitors against Alzheimer disease.
Acta Crystallogr.,Sect.F, 71:986-992, 2015

PubMed Abstract: Recent developments in molecular pathology and genetics have allowed the identification of human glutaminyl cyclase (hQC) among the abnormal proteins involved in many neurodegenerative disorders. Difficulties in obtaining large quantities of pure protein may limit the use of crystallographic screening for drug development on this target. Site-directed mutagenesis experiments have led to the identification of some solvent-exposed residues that are absolutely critical to achieve increased solubility and to avoid precipitation of the enzyme in inclusion bodies when expressed in Escherichia coli. The designed variant Y115E-Y117E has been found to be able to provide large amounts of monodisperse, pure hQC from an E. coli expression system. To validate the use of the artificial construct as a target for large-scale X-ray and NMR screening campaigns in the search for new inhibitors of hQC, the X-ray crystal structures of the hQC Y115E-Y117E variant and of its adduct with the inhibitor PBD-150 were determined.

PubMed: 26249687
DOI: 10.1107/S2053230X15010389

Experimental method

X-RAY DIFFRACTION (1.95 Å)