scholarly journals Exploring the Water-Binding Pocket of the Type II Dehydroquinase Enzyme in the Structure-Based Design of Inhibitors

2014 ◽  
Vol 57 (8) ◽  
pp. 3494-3510 ◽  
Author(s):  
Beatriz Blanco ◽  
Antía Sedes ◽  
Antonio Peón ◽  
José M. Otero ◽  
Mark J. van Raaij ◽  
...  
Keyword(s):  
Binding Pocket ◽  
Type Ii ◽  
Water Binding ◽  
Type Ii Dehydroquinase

scholarly journals Competitive Inhibitors ofHelicobacter pylori Type II Dehydroquinase: Synthesis, Biological Evaluation, and NMR Studies

ChemMedChem ◽  
2008 ◽  
Vol 3 (5) ◽  
pp. 756-770 ◽  
Author(s):  
Cristina Sánchez-Sixto ◽  
Verónica F. V. Prazeres ◽  
Luis Castedo ◽  
Se Won Suh ◽  
Heather Lamb ◽  
...  
Keyword(s):  
Biological Evaluation ◽  
Type Ii ◽  
Nmr Studies ◽  
Competitive Inhibitors ◽  
Type Ii Dehydroquinase

The crystal structure of a type II dehydroquinase fromMycobacterium tuberculosis

1996 ◽  
Vol 52 (a1) ◽  
pp. C115-C115
Author(s):  
D. G. Gourley ◽  
J. R. Coggins ◽  
A. R. Hawkins ◽  
N. W. Isaacs
Keyword(s):  
Crystal Structure ◽  
Type Ii ◽  
Type Ii Dehydroquinase

Crystallization and preliminary X-ray crystallographic analysis of type II dehydroquinase fromHelicobacter pylori

2001 ◽  
Vol 57 (2) ◽  
pp. 279-280 ◽  
Author(s):  
Jae Eun Kwak ◽  
Jae Young Lee ◽  
Byung Woo Han ◽  
Jinho Moon ◽  
Se Hui Sohn ◽  
...  
Keyword(s):  
Crystallographic Analysis ◽  
Type Ii ◽  
X Ray ◽  
Type Ii Dehydroquinase

Rational Design, Synthesis, and Evaluation of Nanomolar Type II Dehydroquinase Inhibitors

ChemMedChem ◽  
2007 ◽  
Vol 2 (7) ◽  
pp. 1015-1029 ◽  
Author(s):  
Richard J. Payne ◽  
Fabienne Peyrot ◽  
Olivier Kerbarh ◽  
Andrew D. Abell ◽  
Chris Abell
Keyword(s):  
Rational Design ◽  
Type Ii ◽  
Design Synthesis ◽  
Type Ii Dehydroquinase

scholarly journals Cloning, sequencing, expression, purification and preliminary characterization of a type II dehydroquinase from Helicobacter pylori

1996 ◽  
Vol 319 (2) ◽  
pp. 559-565 ◽  
Author(s):  
Joanna R BOTTOMLEY ◽  
Christopher L. CLAYTON ◽  
Peter A. CHALK ◽  
Colin KLEANTHOUS
Keyword(s):  
Helicobacter Pylori ◽  
Sequence Data ◽  
Shikimate Pathway ◽  
Cosmid Library ◽  
Type Ii ◽  
Gene Encoding ◽  
Heat Stable ◽  
Plasmid Construct ◽  
H Pylori ◽  
Type Ii Dehydroquinase

A heat-stable dehydroquinase was purified to near homogeneity from a plate-grown suspension of the Gram-negative stomach pathogen Helicobacter pylori, and shown from both its subunit and native molecular masses to be a member of the type II family of dehydroquinases. This was confirmed by N-terminal amino acid sequence data. The gene encoding this activity was isolated following initial identification, by random sequencing of the H. pylori genome, of a 96 bp fragment, the translated sequence of which showed strong identity to a C-terminal region of other type II enzymes. Southern blot analysis of a cosmid library identified several potential clones, one of which complemented an Escherichia coliaroD point mutant strain deficient in host dehydroquinase. The gene encoding the H. pylori type II dehydroquinase (designated aroQ) was sequenced. The translated sequence was identical to the N-terminal sequence obtained directly from the purified protein, and showed strong identity to other members of the type II family of dehydroquinases. The enzyme was readily expressed in E. coli from a plasmid construct from which several milligrams of protein could be isolated, and the molecular mass of the protein was confirmed by electrospray MS. The aroQ gene in H. pylori may function in the central biosynthetic shikimate pathway of this bacterium, thus opening the way for the construction of attenuated strains as potential vaccines as well as offering a new target for selective enzyme inhibition.

Irreversible inhibition of type I dehydroquinase by substrates for type II dehydroquinase

2000 ◽  
Vol 10 (5) ◽  
pp. 407-409 ◽  
Author(s):  
Concepción González Bello ◽  
Joanna M. Harris ◽  
Michael K. Manthey ◽  
John R. Coggins ◽  
Chris Abell
Keyword(s):  
Type I ◽  
Type Ii ◽  
Irreversible Inhibition ◽  
Type Ii Dehydroquinase

scholarly journals NTRK kinase domain mutations in cancer variably impact sensitivity to type I and type II inhibitors

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Romel Somwar ◽  
Nicolle E. Hofmann ◽  
Bryan Smith ◽  
Igor Odintsov ◽  
Morana Vojnic ◽  
...  
Keyword(s):  
Treatment Strategies ◽  
Binding Pocket ◽  
Kinase Domain ◽  
Type I ◽  
Type Ii ◽  
Highly Sensitive ◽  
Selective Targeting ◽  
Inhibitory Potential ◽  
Kinase Domain Mutations ◽  
Mutant Kinase

AbstractTyrosine kinase domains dynamically fluctuate between two main structural forms that are referred to as type I (DFG-in) or type II (DFG-out) conformations. Comprehensive data comparing type I and type II inhibitors are currently lacking for NTRK fusion-driven cancers. Here we used a type II NTRK inhibitor, altiratinib, as a model compound to investigate its inhibitory potential for larotrectinib (type I inhibitor)-resistant mutations in NTRK. Our study shows that a subset of larotrectinib-resistant NTRK1 mutations (V573M, F589L and G667C) retains sensitivity to altiratinib, while the NTRK1V573M and xDFG motif NTRK1G667C mutations are highly sensitive to type II inhibitors, including altiratinib, cabozantinib and foretinib. Moreover, molecular modeling suggests that the introduction of a sulfur moiety in the binding pocket, via methionine or cysteine substitutions, specifically renders the mutant kinase hypersensitive to type II inhibitors. Future precision treatment strategies may benefit from selective targeting of these kinase mutants based on our findings.

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