5ji6: Difference between revisions
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The | ==Potent, Reversible MetAP2 Inhibitors via FBDD== | ||
<StructureSection load='5ji6' size='340' side='right'caption='[[5ji6]], [[Resolution|resolution]] 2.15Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[5ji6]] 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=5JI6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5JI6 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]] 2.15Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6KN:4-(3-METHYLPYRIDIN-4-YL)-6-(TRIFLUOROMETHYL)-1H-INDAZOLE'>6KN</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=5ji6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ji6 OCA], [https://pdbe.org/5ji6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5ji6 RCSB], [https://www.ebi.ac.uk/pdbsum/5ji6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5ji6 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 == | |||
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 <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®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 5ji6" style="background-color:#fffaf0;"></div> | ||
[[Category: | |||
==See Also== | |||
*[[Aminopeptidase 3D structures|Aminopeptidase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Dougan DR]] | |||
[[Category: Lawson JD]] | |||
Latest revision as of 21:52, 20 September 2023
Potent, Reversible MetAP2 Inhibitors via FBDDPotent, Reversible MetAP2 Inhibitors via FBDD
Structural highlights
FunctionMAP2_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. Publication Abstract from PubMedMethionine 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 <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[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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