6lzc

crystal structure of Human Methionine aminopeptidase (HsMetAP1b) in complex with KV-P2-4H-05crystal structure of Human Methionine aminopeptidase (HsMetAP1b) in complex with KV-P2-4H-05

Structural highlights

6lzc 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.
Method:	X-ray diffraction, Resolution 1.35Å
Ligands:	, , , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

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]^[1] ^[2]

Publication Abstract from PubMed

Methionine aminopeptidases (MetAPs) are an important class of enzymes that work co-translationally for the removal of initiator methionine. Chemical inhibition or gene knockdown is lethal to the microbes suggesting that they can be used as antibiotic targets. However, sequence and structural similarity between the microbial and host MetAPs has been a challenge in the identification of selective inhibitors. In this study, we have analyzed several thousands of MetAP sequences and established a pattern of variation in the S1 pocket of the enzyme. Based on this knowledge, we have designed a library of 17 azaindole based hydroxamic acid derivatives which selectively inhibited the MetAP from H. pylori compared to the human counterpart. Structural studies provided the molecular basis for the selectivity.

Selective inhibition of Helicobacter pylori methionine aminopeptidase by azaindole hydroxamic acid derivatives: Design, synthesis, in vitro biochemical and structural studies.,Bala S, Yellamanda KV, Kadari A, Ravinuthala VSU, Kattula B, Singh OV, Gundla R, Addlagatta A Bioorg Chem. 2021 Jul 21;115:105185. doi: 10.1016/j.bioorg.2021.105185. PMID:34329997^[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
↑ Bala S, Yellamanda KV, Kadari A, Ravinuthala VSU, Kattula B, Singh OV, Gundla R, Addlagatta A. Selective inhibition of Helicobacter pylori methionine aminopeptidase by azaindole hydroxamic acid derivatives: Design, synthesis, in vitro biochemical and structural studies. Bioorg Chem. 2021 Jul 21;115:105185. doi: 10.1016/j.bioorg.2021.105185. PMID:34329997 doi:http://dx.doi.org/10.1016/j.bioorg.2021.105185

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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] Bala S, Yellamanda KV, Kadari A, Ravinuthala VSU, Kattula B, Singh OV, Gundla R, Addlagatta A. Selective inhibition of Helicobacter pylori methionine aminopeptidase by azaindole hydroxamic acid derivatives: Design, synthesis, in vitro biochemical and structural studies. Bioorg Chem. 2021 Jul 21;115:105185. doi: 10.1016/j.bioorg.2021.105185. PMID:34329997 doi:http://dx.doi.org/10.1016/j.bioorg.2021.105185

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