4P4I

X-ray structure of human glutamate carboxypeptidase II (GCPII) in complex with a phosphoramidate inhibitor T33

Summary for 4P4I

• Entry DOI: 10.2210/pdb4p4i/pdb
• Related: 4P4B 4P4D 4P4E 4P4F 4P4J
• Descriptor: Glutamate carboxypeptidase 2, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, alpha-D-mannopyranose-(1-3)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (9 entities in total)
• Functional Keywords: hydrolase
• Biological source: Homo sapiens (Human)
• Cellular location: Cell membrane ; Single-pass type II membrane protein . Isoform PSMA': Cytoplasm: Q04609
• Total number of polymer chains: 1
• Total formula weight: 82924.90

Authors

Barinka, C. (deposition date: 2014-03-12, release date: 2015-05-20, Last modification date: 2020-07-29)

Primary citation

Novakova, Z.,Cerny, J.,Choy, C.J.,Nedrow, J.R.,Choi, J.K.,Lubkowski, J.,Berkman, C.E.,Barinka, C.
Design of composite inhibitors targeting glutamate carboxypeptidase II: the importance of effector functionalities.
Febs J., 283:130-143, 2016

PubMed Abstract: 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. 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 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.

PubMed: 26460595
DOI: 10.1111/febs.13557

Experimental method

X-RAY DIFFRACTION (1.87 Å)