View source for 5jhu


==Potent, Reversible MetAP2 Inhibitors via FBDD==
<StructureSection load='5jhu' size='340' side='right'caption='[[5jhu]], [[Resolution|resolution]] 1.80&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5jhu]] 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=5JHU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5JHU 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]] 1.8&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6KO:[(2R)-1-([1,2,4]TRIAZOLO[1,5-A]PYRIMIDIN-7-YL)PYRROLIDIN-2-YL]METHYL+2-METHOXYBENZOATE'>6KO</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</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=5jhu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5jhu OCA], [https://pdbe.org/5jhu PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5jhu RCSB], [https://www.ebi.ac.uk/pdbsum/5jhu PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5jhu 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.
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== Publication Abstract from PubMed ==
Methionine aminopeptidase 2 (MetAP2) is an enzyme that cleaves an N-terminal methionine residue from a number of newly synthesized proteins. Pre-clinical and clinical studies suggest that MetAP2 inhibitors could be used as a novel treatment for obesity. Herein we describe our use of fragment screening methods and structural biology to quickly identify and elaborate an indazole fragment into a series of reversible MetAP2 inhibitors with &lt;10nM potency, excellent selectivity, and favorable in vitro safety profiles.

Discovery of potent, reversible MetAP2 inhibitors via fragment based drug discovery and structure based drug design-Part 1.,Cheruvallath Z, Tang M, McBride C, Komandla M, Miura J, Ton-Nu T, Erikson P, Feng J, Farrell P, Lawson JD, Vanderpool D, Wu Y, Dougan DR, Plonowski A, Holub C, Larson C Bioorg Med Chem Lett. 2016 Jun 15;26(12):2774-8. doi: 10.1016/j.bmcl.2016.04.073., Epub 2016 Apr 25. PMID:27155900<ref>PMID:27155900</ref>

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

==See Also==
*[[Aminopeptidase 3D structures|Aminopeptidase 3D structures]]
== References ==
<references/>
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Dougan DR]]