The structure of the human glutaminyl cyclase–SEN177 complex indicates routes for developing new potent inhibitors as possible agents for the treatment of neurological disorders

Q3 · CHEMISTRY

Article

Author: Benvenuti, Manuela ; Pozzi, Cecilia ; Mangani, Stefano ; Di Pisa, Flavio

Recent evidence links the role of human glutaminyl cyclase (hQC) to the amyloidogenic process involved in Alzheimer's disease (AD). hQC is a zinc enzyme present in neuronal tissue and its activity is responsible for the cyclization of N-terminal Gln or Glu β-amyloid peptides, leading to N-pyroglutamic acid peptides (pE-Aβ) that is probably a crucial event in the initiation and progress of the disease. Indeed, pE-containing peptides exhibit an elevated neurotoxicity and a tendency to aggregate. These observations render hQC inhibition an attractive strategy for developing new molecules active against AD. We present here the crystal structure of hQC in complex with SEN177, a newly designed molecule. The SEN177-binding mode to hQC differs from that of the known hQC inhibitors. SEN177 K_i on hQC is 20 nM, comparable or better than that of the most potent known hQC inhibitors PBD150 and PQ912. In addition, SEN177 already demonstrated relevant pharmacological properties in in vivo models of Huntington's disease. All these properties make SEN177 an important scaffold for developing molecules acting on AD and related diseases.

01 Aug 2015·Acta Crystallographica Section F Structural Biology CommunicationsQ4 · BIOLOGY

The soluble Y115E–Y117E variant of human glutaminyl cyclase is a valid target for X-ray and NMR screening of inhibitors against Alzheimer disease

Q4 · BIOLOGY

Article

Author: Marconi, Guido ; Benvenuti, Manuela ; Andreini, Matteo ; DiPisa, Flavio ; Pozzi, Cecilia ; Mangani, Stefano

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 inEscherichia coli. The designed variant Y115E–Y117E has been found to be able to provide large amounts of monodisperse, pure hQC from anE. coliexpression 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.

01 Mar 2014·Acta Crystallographica Section D Biological Crystallography

Structural and functional analyses of a glutaminyl cyclase from Ixodes scapularis reveal metal-independent catalysis and inhibitor binding

Article

Author: Huang, Kai-Fa ; Karim, Shahid ; Hsu, Hui-Ling ; Wang, Andrew H-J

Glutaminyl cyclases (QCs) from mammals and Drosophila are zinc-dependent enzymes that catalyze N-terminal pyroglutamate formation of numerous proteins and peptides. These enzymes have been found to be critical for the oviposition and embryogenesis of ticks, implying that they are possible physiological targets for tick control. Here, 1.10–1.15 Å resolution structures of a metal-independent QC from the black-legged tick Ixodes scapularis (Is-QC) are reported. The structures exhibit the typical scaffold of mammalian QCs but have two extra disulfide bridges that stabilize the central β-sheet, resulting in an increased thermal stability. Is-QC contains ∼0.5 stoichiometric zinc ions, which could be removed by 1 mM EDTA. Compared with the Zn-bound form, apo-Is-QC has a nearly identical active-site structure and stability, but unexpectedly possesses significantly increased QC activities towards both synthetic and physiological substrates. Enzyme-kinetic analysis revealed that apo-Is-QC has a stronger substrate-binding affinity, suggesting that bound zinc interferes with substrate binding during catalysis. The structures of Is-QC bound to the inhibitor PBD150 revealed similar binding modes to both forms of Is-QC, with the exception of the inhibitor imidazole ring, which is consistent with the comparable inhibition activities of the inhibitor towards both forms of Is-QC. These findings have implications for the design of new QC inhibitors.

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Nervous System Diseases	Discovery	DE	Vivoryon Therapeutics NV	-

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