4iu6

Human Methionine Aminopeptidase in complex with FZ1: Pyridinylquinazolines Selectively Inhibit Human Methionine Aminopeptidase-1

spinqualitylabelsall models 4iu6, resolution 1.90Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4iu6 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. Ligands: CO, FZ1, K, SO4 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 Methionine aminopeptidases (MetAPs), which remove the initiator methionine from nascent peptides, are essential in all organisms. While MetAP2 has been demonstrated to be a therapeutic target for inhibiting angiogenesis in mammals, MetAP1 seems to be vital for cell proliferation. Our earlier efforts identified two structural classes of human MetAP1 (HsMetAP1)-selective inhibitors (1-4), but all of them failed to inhibit cellular HsMetAP1. Using Mn(II) or Zn(II) to activate HsMetAP1, we found that 1-4 could only effectively inhibit purified HsMetAP1 in the presence of physiologically unachievable concentrations of Co(II). In an effort to seek Co(II)-independent inhibitors, a novel structural class containing a 2-(pyridin-2-yl)quinazoline core has been discovered. Many compounds in this class potently and selectively inhibited HsMetAP1 without Co(II). Subsequently, we demonstrated that 11j, an auxiliary metal-dependent inhibitor, effectively inhibited HsMetAP1 in primary cells. This is the first report that an HsMetAP1-selective inhibitor is effective against its target in cells. Pyridinylquinazolines selectively inhibit human methionine aminopeptidase-1 in cells.,Zhang F, Bhat S, Gabelli SB, Chen X, Miller MS, Nacev BA, Cheng YL, Meyers DJ, Tenney K, Shim JS, Crews P, Amzel LM, Ma D, Liu JO J Med Chem. 2013 May 23;56(10):3996-4016. doi: 10.1021/jm400227z. Epub 2013 May, 1. PMID:23634668 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Aminopeptidase 3D structures

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