5yr4

Human methionine aminopeptidase type 1b (F309M mutant) in complex with TNP470

spinqualitylabelsall models 5yr4, resolution 1.82Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5yr4 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 1.82Å Ligands: CO, GOL, K, TN4 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] Publication Abstract from PubMed Natural product ovalicin and its synthetic derivative TNP-470 have been extensively studied for their anti-angiogenic property, and the later reached phase 3 clinical trials. They covalently modify the conserved histidine in Type 2 methionine aminopeptidases (MetAPs) at nanomolar concentrations. Even though a similar mechanism is possible in Type 1 human MetAP, it is inhibited only at millimolar concentration. In this study, we have discovered two Type 1 wild type MetAPs ( S. pneumoniae and E. faecalis ) that are inhibited at low micromolar to nanomolar concentrations, and established the molecular mechanism. F309 in the active site of human Type 1 MetAP ( Hs MetAP1b) seems to be the key to the resistance, while newly identified ovalicin sensitive Type 1 MetAPs have a methionine or isoleucine at this position. Type 2 human MetAP ( Hs MetAP2) also has an isoleucine (I338) in the analogous position. Ovalicin inhibited F309M and F309I mutants of human MetAP1b at low micromolar concentration. MD simulations suggest that ovalicin is not stably placed in the active site of wild type MetAP1b before the covalent modification. In the case of F309M mutant and human Type 2 MetAP, molecule spends more time in the active site providing time for covalent modification. Discovery of Natural Product Ovalicin Sensitive Type 1 Methionine Aminopeptidases: Molecular and Structural Basis.,Pillalamarri V, Arya T, Haque N, Bala SC, Marapaka AK, Addlagatta A Biochem J. 2019 Mar 5. pii: BCJ20180874. doi: 10.1042/BCJ20180874. PMID:30837307 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Aminopeptidase 3D structures

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