1b6a

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HUMAN METHIONINE AMINOPEPTIDASE 2 COMPLEXED WITH TNP-470HUMAN METHIONINE AMINOPEPTIDASE 2 COMPLEXED WITH TNP-470

Structural highlights

1b6a 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:,
Activity:Methionyl aminopeptidase, with EC number 3.4.11.18
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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

The fungal metabolite fumagillin suppresses the formation of new blood vessels, and a fumagillin analog is currently in clinical trials as an anticancer agent. The molecular target of fumagillin is methionine aminopeptidase-2 (MetAP-2). A 1.8 A resolution crystal structure of free and inhibited human MetAP-2 shows a covalent bond formed between a reactive epoxide of fumagillin and histidine-231 in the active site of MetAP-2. Extensive hydrophobic and water-mediated polar interactions with other parts of fumagillin provide additional affinity. Fumagillin-based drugs inhibit MetAP-2 but not MetAP-1, and the three-dimensional structure also indicates the likely determinants of this specificity. The structural basis for fumagillin's potency and specificity forms the starting point for structure-based drug design.

Structure of human methionine aminopeptidase-2 complexed with fumagillin.,Liu S, Widom J, Kemp CW, Crews CM, Clardy J Science. 1998 Nov 13;282(5392):1324-7. PMID:9812898[9]

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

References

  1. ↑ 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
  2. ↑ 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
  3. ↑ 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
  4. ↑ 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
  5. ↑ 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
  6. ↑ 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
  7. ↑ 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
  8. ↑ 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
  9. ↑ Liu S, Widom J, Kemp CW, Crews CM, Clardy J. Structure of human methionine aminopeptidase-2 complexed with fumagillin. Science. 1998 Nov 13;282(5392):1324-7. PMID:9812898

1b6a, resolution 1.60Å

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