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| | {{STRUCTURE_3bhx| PDB=3bhx | SCENE= }} | | {{STRUCTURE_3bhx| PDB=3bhx | SCENE= }} |
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| - | '''X-ray structure of human glutamate carboxypeptidase II (GCPII) in complex with a transition state analog of Asp-Glu'''
| + | ===X-ray structure of human glutamate carboxypeptidase II (GCPII) in complex with a transition state analog of Asp-Glu=== |
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| - | ==Overview==
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| - | Human glutamate carboxypeptidase II (GCPII) is involved in neuronal signal transduction and intestinal folate absorption by means of the hydrolysis of its two natural substrates, N-acetyl-aspartyl-glutamate and folyl-poly-gamma-glutamates, respectively. During the past years, tremendous efforts have been made toward the structural analysis of GCPII. Crystal structures of GCPII in complex with various ligands have provided insight into the binding of these ligands, particularly to the S1' site of the enzyme. In this article, we have extended structural characterization of GCPII to its S1 site by using dipeptide-based inhibitors that interact with both S1 and S1' sites of the enzyme. To this end, we have determined crystal structures of human GCPII in complex with phosphapeptide analogs of folyl-gamma-glutamate, aspartyl-glutamate, and gamma-glutamyl-glutamate, refined at 1.50, 1.60, and 1.67 A resolution, respectively. The S1 pocket of GCPII could be accurately defined and analyzed for the first time, and the data indicate the importance of Asn519, Arg463, Arg534, and Arg536 for recognition of the penultimate (i.e., P1) substrate residues. Direct interactions between the positively charged guanidinium groups of Arg534 and Arg536 and a P1 moiety of a substrate/inhibitor provide mechanistic explanation of GCPII preference for acidic dipeptides. Additionally, observed conformational flexibility of the Arg463 and Arg536 side chains likely regulates GCPII affinity toward different inhibitors and modulates GCPII substrate specificity. The biochemical experiments assessing the hydrolysis of several GCPII substrate derivatives modified at the P1 position, also included in this report, further complement and extend conclusions derived from the structural analysis. The data described here form an a solid foundation for the structurally aided design of novel low-molecular-weight GCPII inhibitors and imaging agents.
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| | + | (as it appears on PubMed at http://www.pubmed.gov), where 18234225 is the PubMed ID number. |
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| | ==About this Structure== | | ==About this Structure== |
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| | [[Category: Transmembrane]] | | [[Category: Transmembrane]] |
| | [[Category: Zinc]] | | [[Category: Zinc]] |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 20:47:02 2008'' | + | |
| | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Jul 29 07:13:12 2008'' |
Revision as of 04:13, 29 July 2008
Template:STRUCTURE 3bhx
X-ray structure of human glutamate carboxypeptidase II (GCPII) in complex with a transition state analog of Asp-Glu
Template:ABSTRACT PUBMED 18234225
About this Structure
3BHX is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Structural basis of interactions between human glutamate carboxypeptidase II and its substrate analogs., Barinka C, Hlouchova K, Rovenska M, Majer P, Dauter M, Hin N, Ko YS, Tsukamoto T, Slusher BS, Konvalinka J, Lubkowski J, J Mol Biol. 2008 Mar 7;376(5):1438-50. Epub 2008 Jan 5. PMID:18234225
Page seeded by OCA on Tue Jul 29 07:13:12 2008
