Design of composite inhibitors targeting glutamate carboxypeptidase II: the importance of effector functionalities

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F86652036%3A_____%2F16%3A00456227" target="_blank" >RIV/86652036:_____/16:00456227 - isvavai.cz</a>

Result on the web

<a href="http://dx.doi.org/10.1111/febs.13557" target="_blank" >http://dx.doi.org/10.1111/febs.13557</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1111/febs.13557" target="_blank" >10.1111/febs.13557</a>

Result language

angličtina

Original language name

Design of composite inhibitors targeting glutamate carboxypeptidase II: the importance of effector functionalities

Original language description

Inhibitors targeting human glutamate carboxypeptidase II (GCPII) typically consist of a P1 glutamate-derived binding module, which warrants the high affinity and specificity, linked to an effector function that is positioned within the entrance funnel ofthe enzyme. Here we present a comprehensive structural and computational study aimed at dissecting the importance of the effector function for GCPII binding and affinity. To this end we determined crystal structures of human GCPII in complex with a series of phosphoramidate-based inhibitors harboring effector functions of diverse physicochemical characteristics. Our data show that higher binding affinities of phosphoramidates, compared to matching phosphonates, are linked to the presence of additionalhydrogen bonds between Glu424 and Gly518 of the enzyme and the amide group of the phosphoramidate. While the positioning of the P1 glutamate-derived module within the S1 pocket of GCPII is invariant, interaction interfaces between effecto

Czech name

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Czech description

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Type

J_x - Unclassified - Peer-reviewed scientific article (Jimp, Jsc and Jost)

CEP classification

EB - Genetics and molecular biology

OECD FORD branch

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Project

Result was created during the realization of more than one project. More information in the Projects tab.

Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2016

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

FEBS Journal

ISSN

1742-464X

e-ISSN

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Volume of the periodical

283

Issue of the periodical within the volume

1

Country of publishing house

GB - UNITED KINGDOM

Number of pages

14

Pages from-to

130-143

UT code for WoS article

000368034600010

EID of the result in the Scopus database

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