View source for 5lyw


==CRYSTAL STRUCTURE OF HUMAN METHIONINE AMINOPEPTIDASE-2 IN COMPLEX; WITH AN INHIBITOR 6-((R)-2-o-Tolyloxymethyl-pyrrolidin-1-yl)-9H-purine==
<StructureSection load='5lyw' size='340' side='right'caption='[[5lyw]], [[Resolution|resolution]] 1.69&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5lyw]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5LYW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5LYW FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.69&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=7BH:6-[(2~{R})-2-[(2-methylphenoxy)methyl]pyrrolidin-1-yl]-7~{H}-purine'>7BH</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5lyw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5lyw OCA], [https://pdbe.org/5lyw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5lyw RCSB], [https://www.ebi.ac.uk/pdbsum/5lyw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5lyw ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/MAP2_HUMAN MAP2_HUMAN] Cotranslationally removes the N-terminal methionine from nascent proteins. The N-terminal methionine is often cleaved when the second residue in the primary sequence is small and uncharged (Met-Ala-, Cys, Gly, Pro, Ser, Thr, or Val). The catalytic activity of human METAP2 toward Met-Val peptides is consistently two orders of magnitude higher than that of METAP1, suggesting that it is responsible for processing proteins containing N-terminal Met-Val and Met-Thr sequences in vivo.  Protects eukaryotic initiation factor EIF2S1 from translation-inhibiting phosphorylation by inhibitory kinases such as EIF2AK2/PKR and EIF2AK1/HCR. Plays a critical role in the regulation of protein synthesis.
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
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 (IC50: 1muM) led to the most potent compound 27 (IC50: 0.038muM), 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 degrees flip for the triazolo[1,5-a]pyrimdine bicyclic template.

Novel reversible methionine aminopeptidase-2 (MetAP-2) inhibitors based on purine and related bicyclic templates.,Heinrich T, Buchstaller HP, Cezanne B, Rohdich F, Bomke J, Friese-Hamim M, Krier M, Knochel T, Musil D, Leuthner B, Zenke F Bioorg Med Chem Lett. 2017 Feb 1;27(3):551-556. doi: 10.1016/j.bmcl.2016.12.019. , Epub 2016 Dec 8. PMID:27998678<ref>PMID:27998678</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5lyw" style="background-color:#fffaf0;"></div>

==See Also==
*[[Aminopeptidase 3D structures|Aminopeptidase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Heinrich T]]
[[Category: Knoechel T]]
[[Category: Lehmann M]]
[[Category: Musil D]]