4hxx

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==Pyridinylpyrimidines selectively inhibit human methionine aminopeptidase-1==
==Pyridinylpyrimidines selectively inhibit human methionine aminopeptidase-1==
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<StructureSection load='4hxx' size='340' side='right' caption='[[4hxx]], [[Resolution|resolution]] 2.09&Aring;' scene=''>
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<StructureSection load='4hxx' size='340' side='right'caption='[[4hxx]], [[Resolution|resolution]] 2.09&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[4hxx]] 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=4HXX OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4HXX FirstGlance]. <br>
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<table><tr><td colspan='2'>[[4hxx]] 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=4HXX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4HXX 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=1AY:(1R)-N~2~-[5-CHLORO-2-(5-CHLOROPYRIDIN-2-YL)-6-METHYLPYRIMIDIN-4-YL]-1-PHENYL-N~1~-(4-PHENYLBUTYL)ETHANE-1,2-DIAMINE'>1AY</scene>, <scene name='pdbligand=CO:COBALT+(II)+ION'>CO</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.09&#8491;</td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">KIAA0094, METAP1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1AY:(1R)-N~2~-[5-CHLORO-2-(5-CHLOROPYRIDIN-2-YL)-6-METHYLPYRIMIDIN-4-YL]-1-PHENYL-N~1~-(4-PHENYLBUTYL)ETHANE-1,2-DIAMINE'>1AY</scene>, <scene name='pdbligand=CO:COBALT+(II)+ION'>CO</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></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'>[https://proteopedia.org/fgij/fg.htm?mol=4hxx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4hxx OCA], [https://pdbe.org/4hxx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4hxx RCSB], [https://www.ebi.ac.uk/pdbsum/4hxx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4hxx ProSAT]</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=4hxx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4hxx OCA], [http://pdbe.org/4hxx PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4hxx RCSB], [http://www.ebi.ac.uk/pdbsum/4hxx PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4hxx ProSAT]</span></td></tr>
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</table>
</table>
== Function ==
== Function ==
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[[http://www.uniprot.org/uniprot/AMPM1_HUMAN AMPM1_HUMAN]] Removes the N-terminal methionine from nascent proteins. Required for normal progression through the cell cycle.<ref>PMID:16274222</ref> <ref>PMID:17114291</ref>
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[https://www.uniprot.org/uniprot/MAP11_HUMAN MAP11_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). Required for normal progression through the cell cycle.[HAMAP-Rule:MF_03174]<ref>PMID:16274222</ref> <ref>PMID:17114291</ref>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Cellular protein synthesis is initiated with methionine in eukaryotes with few exceptions. Methionine aminopeptidases (MetAPs) which catalyze the process of N-terminal methionine excision are essential for all organisms. In mammals, type 2 MetAP (MetAP2) is known to be important for angiogenesis, while type 1 MetAP (MetAP1) has been shown to play a pivotal role in cell proliferation. Our previous high-throughput screening of a commercial compound library uncovered a novel class of inhibitors for both human MetAP1 (HsMetAP1) and human MetAP2 (HsMetAP2). This class of inhibitors contains a pyridinylpyrimidine core. To understand the structure-activity relationship (SAR) and to search for analogues of 2 with greater potency and higher HsMetAP1-selectivity, a total of 58 analogues were acquired through either commercial source or by in-house synthesis and their inhibitory activities against HsMetAP1 and HsMetAP2 were determined. Through this systematic medicinal chemistry analysis, we have identified (1) 5-chloro-6-methyl-2-pyridin-2-ylpyrimidine as the minimum element for the inhibition of HsMetAP1; (2) 5'-chloro as the favored substituent on the pyridine ring for the enhanced potency against HsMetAP1; and (3) long C4 side chains as the essentials for higher HsMetAP1-selectivity. At the end of our SAR campaign, 25b, 25c, 26d and 30a-30c are among the most selective and potent inhibitors of purified HsMetAP1 reported to date. In addition, we also performed crystallographic analysis of one representative inhibitor (26d) in complex with N-terminally truncated HsMetAP1.
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Pyridinylpyrimidines selectively inhibit human methionine aminopeptidase-1.,Zhang P, Yang X, Zhang F, Gabelli SB, Wang R, Zhang Y, Bhat S, Chen X, Furlani M, Amzel LM, Liu JO, Ma D Bioorg Med Chem. 2013 Feb 21. pii: S0968-0896(13)00147-8. doi:, 10.1016/j.bmc.2013.02.023. PMID:23507151<ref>PMID:23507151</ref>
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==See Also==
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*[[Aminopeptidase 3D structures|Aminopeptidase 3D structures]]
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 4hxx" style="background-color:#fffaf0;"></div>
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== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Human]]
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[[Category: Homo sapiens]]
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[[Category: Methionyl aminopeptidase]]
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[[Category: Large Structures]]
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[[Category: Amzel, L M]]
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[[Category: Amzel LM]]
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[[Category: Gabelli, S B]]
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[[Category: Gabelli SB]]
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[[Category: Liu, J]]
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[[Category: Liu J]]
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[[Category: Zhang, F]]
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[[Category: Zhang F]]
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[[Category: Aminopeptidase]]
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[[Category: Cell cycle]]
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[[Category: Hydrolase-hydrolase inhibitor complex]]
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[[Category: Pyridinylpyrimidine]]
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[[Category: Pyrimidine]]
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[[Category: Pyrimidyl group]]
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Current revision

Pyridinylpyrimidines selectively inhibit human methionine aminopeptidase-1

PDB ID 4hxx

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