4PNC

E. COLI METHIONINE AMINOPEPTIDASE IN COMPLEX WITH INHIBITOR 7-METHOXY-2-METHYLEN-3,4-DIHYDRONAPHTHALEN-1(2H)-ONE

Summary for 4PNC

• Entry DOI: 10.2210/pdb4pnc/pdb
• Related: 1XNZ 1YVM 3MAT
• Descriptor: Methionine aminopeptidase, (2S)-7-methoxy-2-methyl-3,4-dihydronaphthalen-1(2H)-one, COBALT (II) ION, ... (5 entities in total)
• Functional Keywords: hydrolase(alpha-aminoacylpeptide), metal complex, methionine aminopeptidase, covalent inhibitor, 1-tetralone, hydrolase
• Biological source: Escherichia coli
• Total number of polymer chains: 1
• Total formula weight: 29731.80

Authors

Scheidig, A.J.,Altmeyer, M.,Klein, C.D. (deposition date: 2014-05-23, release date: 2014-07-23, Last modification date: 2023-12-27)

Primary citation

Altmeyer, M.,Amtmann, E.,Heyl, C.,Marschner, A.,Scheidig, A.J.,Klein, C.D.
Beta-aminoketones as prodrugs for selective irreversible inhibitors of type-1 methionine aminopeptidases.
Bioorg.Med.Chem.Lett., 24:5310-5314, 2014

PubMed Abstract: We identified and characterized β-aminoketones as prodrugs for irreversible MetAP inhibitors that are selective for the MetAP-1 subtype. β-Aminoketones with certain structural features form α,β-unsaturated ketones under physiological conditions, which bind covalently and selectively to cysteines in the S1 pocket of MetAP-1. The binding mode was confirmed by X-ray crystallography and assays with the MetAPs from Escherichia coli, Staphylococcus aureus and both human isoforms. The initially identified tetralone derivatives showed complete selectivity for E. coli MetAP versus human MetAP-1 and MetAP-2. Rational design of indanone analogs yielded compounds with selectivity for the human type-1 versus the human type-2 MetAP.

PubMed: 25293447
DOI: 10.1016/j.bmcl.2014.09.047

Experimental method

X-RAY DIFFRACTION (1.54 Å)