View source for 5lyx


==CRYSTAL STRUCTURE OF HUMAN METHIONINE AMINOPEPTIDASE-2 IN COMPLEX; WITH AN INHIBITOR 5-((R)-1-[1,2,4]Triazolo[1,5-a]pyrimidin-7-yl-pyrrolidin-2-ylmethoxy)-isoquinoline==
<StructureSection load='5lyx' size='340' side='right' caption='[[5lyx]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5lyx]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5LYX OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5LYX FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=7BF:5-[[(2~{R})-1-([1,2,4]triazolo[1,5-a]pyrimidin-7-yl)pyrrolidin-2-yl]methoxy]isoquinoline'>7BF</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene></td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Methionyl_aminopeptidase Methionyl aminopeptidase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.11.18 3.4.11.18] </span></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5lyx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5lyx OCA], [http://pdbe.org/5lyx PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5lyx RCSB], [http://www.ebi.ac.uk/pdbsum/5lyx PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5lyx ProSAT]</span></td></tr>
</table>
== Function ==
[[http://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. 
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== 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 5lyx" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Methionyl aminopeptidase]]
[[Category: Heinrich, T]]
[[Category: Lehmann, M]]
[[Category: Musil, D]]
[[Category: Hydrolase]]
[[Category: Hydrolase- hydrolase inhibitor complex]]
[[Category: Metal ion binding]]
[[Category: Peptidase]]
[[Category: Proteolysis]]