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5jfr

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Revision as of 07:47, 10 June 2020

Potent, Reversible MetAP2 Inhibitors via Fragment Based Drug Discovery

Structural highlights

5jfr is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, , ,
Related:	5jhu, 5ji6
Gene:	METAP2, MNPEP, P67EIF2 (HUMAN)
Activity:	Methionyl aminopeptidase, with EC number 3.4.11.18
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[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.

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. 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.

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^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ McBride C, Cheruvallath Z, Komandla M, Tang M, Farrell P, Lawson JD, Vanderpool D, Wu Y, Dougan DR, Plonowski A, Holub C, Larson C. Discovery of potent, reversible MetAP2 inhibitors via fragment based drug discovery and structure based drug design-Part 2. 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 doi:http://dx.doi.org/10.1016/j.bmcl.2016.04.072

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5jfr"

@@ Line 1: / Line 1: @@
 ==Potent, Reversible MetAP2 Inhibitors via Fragment Based Drug Discovery==
-<StructureSection load='5jfr' size='340' side='right' caption='[[5jfr]], [[Resolution|resolution]] 1.60&Aring;' scene=''>
+<StructureSection load='5jfr' size='340' side='right'caption='[[5jfr]], [[Resolution|resolution]] 1.60&Aring;' scene=''>
 == Structural highlights ==
-<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>
+<table><tr><td colspan='2'>[[5jfr]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. 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://proteopedia.org/fgij/fg.htm?mol=5JFR FirstGlance]. <br>
-</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>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><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>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5jhu|5jhu]], [[5ji6|5ji6]]</td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">METAP2, MNPEP, P67EIF2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=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>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/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], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5jfr ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 20: / Line 21: @@
 </div>
 <div class="pdbe-citations 5jfr" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Aminopeptidase 3D structures|Aminopeptidase 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
+[[Category: Human]]
+[[Category: Large Structures]]
 [[Category: Methionyl aminopeptidase]]
 [[Category: Dougan, D R]]

5jfr

From Proteopedia

Revision as of 07:47, 10 June 2020

Potent, Reversible MetAP2 Inhibitors via Fragment Based Drug Discovery

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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