HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

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

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.
AuthorsFlavio DiPisa, Cecilia Pozzi, Manuela Benvenuti, Matteo Andreini, Guido Marconi, Stefano Mangani
JournalActa crystallographica. Section F, Structural biology communications (Acta Crystallogr F Struct Biol Commun) Vol. 71 Issue Pt 8 Pg. 986-92 (Aug 2015) ISSN: 2053-230X [Electronic] United States
PMID26249687 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Enzyme Inhibitors
  • Imidazoles
  • Nootropic Agents
  • Recombinant Fusion Proteins
  • Aminoacyltransferases
  • glutaminyl-peptide cyclotransferase
  • Thiourea
Topics
  • Alzheimer Disease (drug therapy, enzymology)
  • Amino Acid Motifs
  • Aminoacyltransferases (antagonists & inhibitors, chemistry, genetics)
  • Cloning, Molecular
  • Crystallization
  • Crystallography, X-Ray
  • Enzyme Inhibitors (chemistry)
  • Escherichia coli (genetics, metabolism)
  • Gene Expression
  • Humans
  • Imidazoles (chemistry)
  • Models, Molecular
  • Molecular Sequence Data
  • Mutation
  • Nootropic Agents (chemistry)
  • Protein Engineering
  • Protein Multimerization
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Recombinant Fusion Proteins (chemistry, genetics)
  • Solubility
  • Structural Homology, Protein
  • Thiourea (analogs & derivatives, chemistry)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: