7a16 | pdb_00007a16

CRYSTAL STRUCTURE OF HUMAN METHIONINE AMINOPEPTIDASE-2 IN COMPLEX WITH AN INHIBITOR GSK2229238A (COMPOUND 43)

spinqualitylabelsall models 7a16, resolution 1.90Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7a16 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: HZE, MN, PO4 Gene: METAP2, MNPEP, P67EIF2 (HUMAN) Activity: Methionyl aminopeptidase, with EC number 3.4.11.18 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 Structure-based led optimisation of orally active reversible Methionine Aminopeptidase-2 (MetAP-2) inhibitors utilising a 'molecular budget' medicinal chemistry strategy is described. The key physicochemical parameters of target molecules (cLogP, molecular size and H-bond donor count) were monitored through straightforward and intuitive use of atom count and distribution. The balance between structure-based design and an awareness of the physico-chemical properties of the compounds synthesised enabled the rapid identification of a potent molecule with good oral pharmacokinetic (PK) characteristics by making fewer, higher quality compounds. The resulting candidate quality molecule was validated in a mechanistic cellular assay and a rodent secondary immunisation model. Structure-based optimisation of orally active & reversible MetAP-2 inhibitors maintaining a tight 'molecular budget'.,Hirst DJ, Brandt M, Bruton G, Christodoulou E, Cutler L, Deeks N, Goodacre JD, Jack T, Lindon M, Miah A, Page K, Parr N, Shukla L, Sims M, Thomas P, Thorpe J, Holmes DS Bioorg Med Chem Lett. 2020 Sep 9:127533. doi: 10.1016/j.bmcl.2020.127533. PMID:32919012 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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