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

Novakova, Zora; Cerny, Jiri; Choy, Cindy J.; Nedrow, Jessie R.; Choi, Joeseph K.; Lubkowski, Jacek; Berkman, Clifford E.; Barinka, Cyril

doi:10.1111/febs.13557

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

Journal Article · Tue Oct 13 00:00:00 EDT 2015 · Federation of European Biochemical Societies (FEBS) Journal

DOI:https://doi.org/10.1111/febs.13557· OSTI ID:1236864

Novakova, Zora ^[1]; Cerny, Jiri ^[1]; Choy, Cindy J. ^[2]; Nedrow, Jessie R. ^[2]; Choi, Joeseph K. ^[2]; Lubkowski, Jacek ^[3]; Berkman, Clifford E. ^[2]; Barinka, Cyril ^[1]

Academy of Sciences of the Czech Republic, Prague (Czech Republic)
Washington State Univ., Pullman, WA (United States)
National Cancer Inst., Bethesda, MD (United States)

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 of the enzyme. In this paper 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 additional hydrogen 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 effector functions and residues lining the entrance funnel are highly varied, with the positively charged arginine patch defined by Arg463, Arg534 and Arg536 being the only ‘hot-spot’ common to several studied complexes. This variability stems in part from the fact that the effector/GCPII interfaces generally encompass isolated areas of nonpolar residues within the entrance funnel and resulting van der Waals contacts lack the directionality typical for hydrogen bonding interactions. The presented data unravel a complexity of binding modes of inhibitors within non-prime site(s) of GCPII and can be exploited for the design of novel GCPII-specific compounds.

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Research Organization:: Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: USDOE; Czech Science Foundation (GACR); National Institutes of Health (NIH); European Regional Development Fund (ERDF)

Grant/Contract Number:: W-31-109-ENG-38; 283570; 301/12/1513

OSTI ID:: 1236864

Journal Information:: Federation of European Biochemical Societies (FEBS) Journal, Vol. 283, Issue 1; ISSN 1742-464X

Publisher:: Federation of European Biochemical SocietiesCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 16 works

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

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Cited By (3)

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