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5jfr

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'''Unreleased structure'''
 
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The entry 5jfr is ON HOLD until Paper Publication
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==Potent, Reversible MetAP2 Inhibitors via Fragment Based Drug Discovery==
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<StructureSection load='5jfr' size='340' side='right' caption='[[5jfr]], [[Resolution|resolution]] 1.60&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[5jfr]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5JFR OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5JFR FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=6KP:7-FLUORO-4-(5-METHYL-3H-IMIDAZO[4,5-B]PYRIDIN-6-YL)-2,4-DIHYDROPYRAZOLO[4,3-B]INDOLE'>6KP</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene></td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5jhu|5jhu]], [[5ji6|5ji6]]</td></tr>
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<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>
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<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=5jfr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5jfr OCA], [http://pdbe.org/5jfr PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5jfr RCSB], [http://www.ebi.ac.uk/pdbsum/5jfr PDBsum]</span></td></tr>
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</table>
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== Function ==
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[[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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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Methionine aminopeptidase-2 (MetAP2) is an enzyme that cleaves an N-terminal methionine residue from a number of newly synthesized proteins. This step is required before they will fold or function correctly. Pre-clinical and clinical studies with a MetAP2 inhibitor suggest that they could be used as a novel treatment for obesity. Herein we describe the discovery of a series of pyrazolo[4,3-b]indoles as reversible MetAP2 inhibitors. A fragment-based drug discovery (FBDD) approach was used, beginning with the screening of fragment libraries to generate hits with high ligand-efficiency (LE). An indazole core was selected for further elaboration, guided by structural information. SAR from the indazole series led to the design of a pyrazolo[4,3-b]indole core and accelerated knowledge-based fragment growth resulted in potent and efficient MetAP2 inhibitors, which have shown robust and sustainable body weight loss in DIO mice when dosed orally.
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Authors: Dougan, D.R., Lawson, J.D.
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Discovery of potent, reversible MetAP2 inhibitors via fragment based drug discovery and structure based drug design-Part 2.,McBride C, Cheruvallath Z, Komandla M, Tang M, 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):2779-83. doi:, 10.1016/j.bmcl.2016.04.072. Epub 2016 Apr 25. PMID:27136719<ref>PMID:27136719</ref>
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Description: Potent, Reversible MetAP2 Inhibitors via Fragment Based Drug Discovery
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[Category: Unreleased Structures]]
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</div>
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[[Category: Lawson, J.D]]
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<div class="pdbe-citations 5jfr" style="background-color:#fffaf0;"></div>
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[[Category: Dougan, D.R]]
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== References ==
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<references/>
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__TOC__
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</StructureSection>
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[[Category: Methionyl aminopeptidase]]
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[[Category: Dougan, D R]]
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[[Category: Lawson, J D]]
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[[Category: Hydrolase]]
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[[Category: Hydrolase-hydrolase inhibitor complex]]
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[[Category: Metal ion binding]]
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[[Category: Peptidase]]
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[[Category: Proteolysis]]

Revision as of 23:05, 1 June 2016

Potent, Reversible MetAP2 Inhibitors via Fragment Based Drug Discovery

5jfr, resolution 1.60Å

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