5LYW

CRYSTAL STRUCTURE OF HUMAN METHIONINE AMINOPEPTIDASE-2 IN COMPLEX; WITH AN INHIBITOR 6-((R)-2-o-Tolyloxymethyl-pyrrolidin-1-yl)-9H-purine

Summary for 5LYW

• Entry DOI: 10.2210/pdb5lyw/pdb
• Descriptor: Methionine aminopeptidase 2, 6-[(2~{R})-2-[(2-methylphenoxy)methyl]pyrrolidin-1-yl]-7~{H}-purine, MANGANESE (II) ION, ... (4 entities in total)
• Functional Keywords: hydrolase, peptidase, metal ion binding, proteolysis, hydrolase- hydrolase inhibitor complex
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm : P50579
• Total number of polymer chains: 1
• Total formula weight: 42889.45

Authors

Musil, D.,Heinrich, T.,Knoechel, T.,Lehmann, M. (deposition date: 2016-09-28, release date: 2017-08-16, Last modification date: 2024-05-08)

Primary citation

Heinrich, T.,Buchstaller, H.P.,Cezanne, B.,Rohdich, F.,Bomke, J.,Friese-Hamim, M.,Krier, M.,Knochel, T.,Musil, D.,Leuthner, B.,Zenke, F.
Novel reversible methionine aminopeptidase-2 (MetAP-2) inhibitors based on purine and related bicyclic templates.
Bioorg. Med. Chem. Lett., 27:551-556, 2017

PubMed Abstract: The natural product fumagillin 1 and derivatives like TNP-470 2 or beloranib 3 bind to methionine aminopeptidase 2 (MetAP-2) irreversibly. This enzyme is critical for protein maturation and plays a key role in angiogenesis. In this paper we describe the synthesis, MetAP-2 binding affinity and structural analysis of reversible MetAP-2 inhibitors. Optimization of enzymatic activity of screening hit 10 (IC: 1μM) led to the most potent compound 27 (IC: 0.038μM), with a concomitant improvement in LLE from 2.1 to 4.2. Structural analysis of these MetAP-2 inhibitors revealed an unprecedented conformation of the His339 side-chain imidazole ring being co-planar sandwiched between the imidazole of His331 and the aryl-ether moiety, which is bound to the purine scaffold. Systematic alteration and reduction of H-bonding capability of this metal binding moiety induced an unexpected 180° flip for the triazolo[1,5-a]pyrimdine bicyclic template.

PubMed: 27998678
DOI: 10.1016/j.bmcl.2016.12.019

Experimental method

X-RAY DIFFRACTION (1.69 Å)