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2oaz

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Revision as of 01:38, 12 September 2015

Human Methionine Aminopeptidase-2 Complexed with SB-587094

Structural highlights

2oaz is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Activity:	Methionyl aminopeptidase, with EC number 3.4.11.18
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum

Function

[AMPM2_HUMAN] Removes the N-terminal methionine from nascent proteins. 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.^[1] ^[2] ^[3] ^[4] 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.^[5] ^[6] ^[7] ^[8]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

High-throughput screening for inhibitors of the human metalloprotease, methionine aminopeptidase-2 (MetAP2), identified a potent class of 3-anilino-5-benzylthio-1,2,4-triazole compounds. Efficient array and interative synthesis of triazoles led to rapid SAR development around the aniline, benzylthio, and triazole moeities. Evaluation of these analogs in a human MetAP2 enzyme assay led to the identification of several inhibitors with potencies in the 50-100 picomolar range. The deleterious effects on inhibitor potency by methylation of the anilino-triazole nitrogens, as well as the X-ray crystal structure of triazole 102 bound in the active site of MetAP2, confirm the key interactions between the triazole nitrogens, the active site cobalt atoms, and the His-231 side-chain. The structure has also provided a rationale for interpreting SAR within the triazole series. Key aniline (2-isopropylphenyl) and sulfur substituents (furanylmethyl) identified in the SAR studies led to the identification of potent inhibitors (103 and 104) of endothelial cell proliferation. Triazoles 103 and 104 also exhibited dose-dependent activity in an aortic ring tissue model of angiogenesis highlighting the potential utility of MetAP2 inhibitors as anticancer agents.

Highly potent inhibitors of methionine aminopeptidase-2 based on a 1,2,4-triazole pharmacophore.,Marino JP Jr, Fisher PW, Hofmann GA, Kirkpatrick RB, Janson CA, Johnson RK, Ma C, Mattern M, Meek TD, Ryan MD, Schulz C, Smith WW, Tew DG, Tomazek TA Jr, Veber DF, Xiong WC, Yamamoto Y, Yamashita K, Yang G, Thompson SK J Med Chem. 2007 Aug 9;50(16):3777-85. Epub 2007 Jul 18. PMID:17636946^[9]

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

References

↑ Datta B, Ray MK, Chakrabarti D, Wylie DE, Gupta NK. Glycosylation of eukaryotic peptide chain initiation factor 2 (eIF-2)-associated 67-kDa polypeptide (p67) and its possible role in the inhibition of eIF-2 kinase-catalyzed phosphorylation of the eIF-2 alpha-subunit. J Biol Chem. 1989 Dec 5;264(34):20620-4. PMID:2511207
↑ Xiao Q, Zhang F, Nacev BA, Liu JO, Pei D. Protein N-terminal processing: substrate specificity of Escherichia coli and human methionine aminopeptidases. Biochemistry. 2010 Jul 6;49(26):5588-99. doi: 10.1021/bi1005464. PMID:20521764 doi:http://dx.doi.org/10.1021/bi1005464
↑ Towbin H, Bair KW, DeCaprio JA, Eck MJ, Kim S, Kinder FR, Morollo A, Mueller DR, Schindler P, Song HK, van Oostrum J, Versace RW, Voshol H, Wood J, Zabludoff S, Phillips PE. Proteomics-based target identification: bengamides as a new class of methionine aminopeptidase inhibitors. J Biol Chem. 2003 Dec 26;278(52):52964-71. Epub 2003 Oct 8. PMID:14534293 doi:10.1074/jbc.M309039200
↑ Marino JP Jr, Fisher PW, Hofmann GA, Kirkpatrick RB, Janson CA, Johnson RK, Ma C, Mattern M, Meek TD, Ryan MD, Schulz C, Smith WW, Tew DG, Tomazek TA Jr, Veber DF, Xiong WC, Yamamoto Y, Yamashita K, Yang G, Thompson SK. Highly potent inhibitors of methionine aminopeptidase-2 based on a 1,2,4-triazole pharmacophore. J Med Chem. 2007 Aug 9;50(16):3777-85. Epub 2007 Jul 18. PMID:17636946 doi:10.1021/jm061182w
↑ Datta B, Ray MK, Chakrabarti D, Wylie DE, Gupta NK. Glycosylation of eukaryotic peptide chain initiation factor 2 (eIF-2)-associated 67-kDa polypeptide (p67) and its possible role in the inhibition of eIF-2 kinase-catalyzed phosphorylation of the eIF-2 alpha-subunit. J Biol Chem. 1989 Dec 5;264(34):20620-4. PMID:2511207
↑ Xiao Q, Zhang F, Nacev BA, Liu JO, Pei D. Protein N-terminal processing: substrate specificity of Escherichia coli and human methionine aminopeptidases. Biochemistry. 2010 Jul 6;49(26):5588-99. doi: 10.1021/bi1005464. PMID:20521764 doi:http://dx.doi.org/10.1021/bi1005464
↑ Towbin H, Bair KW, DeCaprio JA, Eck MJ, Kim S, Kinder FR, Morollo A, Mueller DR, Schindler P, Song HK, van Oostrum J, Versace RW, Voshol H, Wood J, Zabludoff S, Phillips PE. Proteomics-based target identification: bengamides as a new class of methionine aminopeptidase inhibitors. J Biol Chem. 2003 Dec 26;278(52):52964-71. Epub 2003 Oct 8. PMID:14534293 doi:10.1074/jbc.M309039200
↑ Marino JP Jr, Fisher PW, Hofmann GA, Kirkpatrick RB, Janson CA, Johnson RK, Ma C, Mattern M, Meek TD, Ryan MD, Schulz C, Smith WW, Tew DG, Tomazek TA Jr, Veber DF, Xiong WC, Yamamoto Y, Yamashita K, Yang G, Thompson SK. Highly potent inhibitors of methionine aminopeptidase-2 based on a 1,2,4-triazole pharmacophore. J Med Chem. 2007 Aug 9;50(16):3777-85. Epub 2007 Jul 18. PMID:17636946 doi:10.1021/jm061182w
↑ Marino JP Jr, Fisher PW, Hofmann GA, Kirkpatrick RB, Janson CA, Johnson RK, Ma C, Mattern M, Meek TD, Ryan MD, Schulz C, Smith WW, Tew DG, Tomazek TA Jr, Veber DF, Xiong WC, Yamamoto Y, Yamashita K, Yang G, Thompson SK. Highly potent inhibitors of methionine aminopeptidase-2 based on a 1,2,4-triazole pharmacophore. J Med Chem. 2007 Aug 9;50(16):3777-85. Epub 2007 Jul 18. PMID:17636946 doi:10.1021/jm061182w

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/2oaz"

@@ Line 5: / Line 5: @@
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CO:COBALT+(II)+ION'>CO</scene>, <scene name='pdbligand=I96:N-(2-ISOPROPYLPHENYL)-3-[(2-THIENYLMETHYL)THIO]-1H-1,2,4-TRIAZOL-5-AMINE'>I96</scene></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=2oaz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2oaz OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2oaz RCSB], [http://www.ebi.ac.uk/pdbsum/2oaz PDBsum]</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=2oaz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2oaz OCA], [http://pdbe.org/2oaz PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2oaz RCSB], [http://www.ebi.ac.uk/pdbsum/2oaz PDBsum]</span></td></tr>
 </table>
 == Function ==
@@ Line 27: / Line 27: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 2oaz" style="background-color:#fffaf0;"></div>
 ==See Also==

2oaz

From Proteopedia

Revision as of 01:38, 12 September 2015

Human Methionine Aminopeptidase-2 Complexed with SB-587094

Structural highlights

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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