期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 25, 期 22, 页码 5232-5236出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2015.09.062
关键词
Carborane; Glutamate carboxypeptidase II; X-ray crystal structure
资金
- Czech Science Foundation [301/12/1513]
- program Biotechnological expert in structural biology and gene expression [CZ.1.07/2.3.00/30.0045]
- BioStruct-X [283570]
- Helmholtz-Zentrum Berlin
- project BIOCEV from ERDF [CZ.1.05/1.1.00/02.0109]
- National Research Foundation of Korea [2012R1A1A1010000, 2014R1A1A2056522, 2014R1A4A1007304]
- National Research Foundation of Korea [2014R1A1A2056522, 2014R1A4A1007304, 2012R1A1A1010000] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
Glutamate carboxypeptidase II (GCPII) is a zinc metalloprotease on the surface of astrocytes which cleaves N-acetylaspartylglutamate to release N-acetylaspartate and glutamate. GCPII inhibitors can decrease glutamate concentration and play a protective role against apoptosis or degradation of brain neurons. Herein, we report the synthesis and structural analysis of novel carborane-based GCPII inhibitors. We determined the X-ray crystal structure of GCPII in complex with a carborane-containing inhibitor at 1.79 angstrom resolution. The X-ray analysis revealed that the bulky closo-carborane cluster is located in the spacious entrance funnel region of GCPII, indicating that the carborane cluster can be further structurally modified to identify promising lead structures of novel GCPII inhibitors. (C) 2015 Elsevier Ltd. All rights reserved.
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