5ji6

From Proteopedia

Potent, Reversible MetAP2 Inhibitors via FBDD

PDB ID 5ji6

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Structural highlights

5ji6 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 2.15Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

MAP2_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). 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. 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.

Publication Abstract from PubMed

Methionine aminopeptidase 2 (MetAP2) is an enzyme that cleaves an N-terminal methionine residue from a number of newly synthesized proteins. Pre-clinical and clinical studies suggest that MetAP2 inhibitors could be used as a novel treatment for obesity. Herein we describe our use of fragment screening methods and structural biology to quickly identify and elaborate an indazole fragment into a series of reversible MetAP2 inhibitors with <10nM potency, excellent selectivity, and favorable in vitro safety profiles.

Discovery of potent, reversible MetAP2 inhibitors via fragment based drug discovery and structure based drug design-Part 1.,Cheruvallath Z, Tang M, McBride C, Komandla M, Miura J, Ton-Nu T, Erikson P, Feng J, Farrell P, Lawson JD, Vanderpool D, Wu Y, Dougan DR, Plonowski A, Holub C, Larson C Bioorg Med Chem Lett. 2016 Jun 15;26(12):2774-8. doi: 10.1016/j.bmcl.2016.04.073., Epub 2016 Apr 25. PMID:27155900^[1]

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

References

↑ Cheruvallath Z, Tang M, McBride C, Komandla M, Miura J, Ton-Nu T, Erikson P, Feng J, Farrell P, Lawson JD, Vanderpool D, Wu Y, Dougan DR, Plonowski A, Holub C, Larson C. Discovery of potent, reversible MetAP2 inhibitors via fragment based drug discovery and structure based drug design-Part 1. Bioorg Med Chem Lett. 2016 Jun 15;26(12):2774-8. doi: 10.1016/j.bmcl.2016.04.073., Epub 2016 Apr 25. PMID:27155900 doi:http://dx.doi.org/10.1016/j.bmcl.2016.04.073