4ikt

Crystal structure of truncated (delta 1-89) human methionine aminopeptidase Type 1 in complex with N1-(5-chloro-6-methyl-2-(pyridin-2-yl)pyrimidin-4-yl)-N2-(5-(trifluoromethyl)pyridin-2-yl)ethane-1,2-diamineCrystal structure of truncated (delta 1-89) human methionine aminopeptidase Type 1 in complex with N1-(5-chloro-6-methyl-2-(pyridin-2-yl)pyrimidin-4-yl)-N2-(5-(trifluoromethyl)pyridin-2-yl)ethane-1,2-diamine

Structural highlights

4ikt 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:	4ikr, 4iks, 4iku
Gene:	METAP1 (HUMAN)
Activity:	Methionyl aminopeptidase, with EC number 3.4.11.18
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[AMPM1_HUMAN] Removes the N-terminal methionine from nascent proteins. Required for normal progression through the cell cycle.^[1] ^[2]

Publication Abstract from PubMed

Methionine aminopeptidases (MetAPs) are essential enzymes that make them good drug targets in cancer and microbial infections. MetAPs remove the initiator methionine from newly synthesized peptides in every living cell. MetAPs are broadly divided into type I and type II classes. Both prokaryotes and eukaryotes contain type I MetAPs, while eukaryotes have additional type II MetAP enzyme. Although several inhibitors have been reported against type I enzymes, subclass specificity is scarce. Here, using the fine differences in the entrance of the active sites of MetAPs from Mycobacterium tuberculosis , Enterococcus faecalis , and human, three hotspots have been identified and pyridinylpyrimidine-based molecules were selected from a commercial source to target these hotspots. In the biochemical evaluation, many of the 38 compounds displayed differential behavior against these three enzymes. Crystal structures of four selected inhibitors in complex with human MetAP1b and molecular modeling studies provided the basis for the binding specificity.

Identification, Biochemical and Structural Evaluation of Species-Specific Inhibitors against Type I Methionine Aminopeptidases.,Kishor C, Arya T, Reddi R, Chen X, Saddanapu V, Marapaka AK, Gumpena R, Ma D, Liu JO, Addlagatta A J Med Chem. 2013 Jun 27. PMID:23767698^[3]

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

References

↑ Addlagatta A, Hu X, Liu JO, Matthews BW. Structural basis for the functional differences between type I and type II human methionine aminopeptidases. Biochemistry. 2005 Nov 15;44(45):14741-9. PMID:16274222 doi:10.1021/bi051691k
↑ Hu X, Addlagatta A, Lu J, Matthews BW, Liu JO. Elucidation of the function of type 1 human methionine aminopeptidase during cell cycle progression. Proc Natl Acad Sci U S A. 2006 Nov 28;103(48):18148-53. Epub 2006 Nov 17. PMID:17114291
↑ Kishor C, Arya T, Reddi R, Chen X, Saddanapu V, Marapaka AK, Gumpena R, Ma D, Liu JO, Addlagatta A. Identification, Biochemical and Structural Evaluation of Species-Specific Inhibitors against Type I Methionine Aminopeptidases. J Med Chem. 2013 Jun 27. PMID:23767698 doi:http://dx.doi.org/10.1021/jm400395p

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OCA

[1] Addlagatta A, Hu X, Liu JO, Matthews BW. Structural basis for the functional differences between type I and type II human methionine aminopeptidases. Biochemistry. 2005 Nov 15;44(45):14741-9. PMID:16274222 doi:10.1021/bi051691k

[2] Hu X, Addlagatta A, Lu J, Matthews BW, Liu JO. Elucidation of the function of type 1 human methionine aminopeptidase during cell cycle progression. Proc Natl Acad Sci U S A. 2006 Nov 28;103(48):18148-53. Epub 2006 Nov 17. PMID:17114291

[3] Kishor C, Arya T, Reddi R, Chen X, Saddanapu V, Marapaka AK, Gumpena R, Ma D, Liu JO, Addlagatta A. Identification, Biochemical and Structural Evaluation of Species-Specific Inhibitors against Type I Methionine Aminopeptidases. J Med Chem. 2013 Jun 27. PMID:23767698 doi:http://dx.doi.org/10.1021/jm400395p

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