1QZY

Human Methionine Aminopeptidase in complex with bengamide inhibitor LAF153 and cobalt

Summary for 1QZY

• Entry DOI: 10.2210/pdb1qzy/pdb
• Descriptor: Methionine aminopeptidase 2, COBALT (II) ION, (E)-(2R,3R,4S,5R)-3,4,5-TRIHYDROXY-2-METHOXY-8,8-DIMETHYL-NON-6-ENOIC ACID ((3S,6R)-6-HYDROXY-2-OXO-AZEPAN-3-YL)-AMIDE, ... (5 entities in total)
• Functional Keywords: hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 53566.00

Authors

Eck, M.J.,Song, H.K.,Morollo, A. (deposition date: 2003-09-18, release date: 2003-11-25, Last modification date: 2024-10-16)

Primary citation

Towbin, H.,Bair, K.W.,DeCaprio, J.A.,Eck, M.J.,Kim, S.,Kinder, F.R.,Morollo, A.,Mueller, D.R.,Schindler, P.,Song, H.K.,van Oostrum, J.,Versace, R.W.,Voshol, H.,Wood, J.,Zabludoff, S.,Phillips, P.E.
Proteomics-based target identification: bengamides as a new class of methionine aminopeptidase inhibitors.
J.Biol.Chem., 278:52964-52971, 2003

PubMed Abstract: LAF389 is a synthetic analogue of bengamides, a class of marine natural products that produce inhibitory effects on tumor growth in vitro and in vivo. A proteomics-based approach has been used to identify signaling pathways affected by bengamides. LAF389 treatment of cells resulted in altered mobility of a subset of proteins on two-dimensional gel electrophoresis. Detailed analysis of one of the proteins, 14-3-3gamma, showed that bengamide treatment resulted in retention of the amino-terminal methionine, suggesting that bengamides directly or indirectly inhibited methionine aminopeptidases (MetAps). Both known MetAps are inhibited by LAF389. Short interfering RNA suppression of MetAp2 also altered amino-terminal processing of 14-3-3gamma. A high resolution structure of human MetAp2 co-crystallized with a bengamide shows that the compound binds in a manner that mimics peptide substrates. Additionally, the structure reveals that three key hydroxyl groups on the inhibitor coordinate the di-cobalt center in the enzyme active site.

PubMed: 14534293
DOI: 10.1074/jbc.M309039200

Experimental method

X-RAY DIFFRACTION (1.6 Å)