2gz5
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Human Type 1 methionine aminopeptidase in complex with ovalicin at 1.1 Ang
OverviewOverview
Methionine aminopeptidases (MetAPs) remove the initiator methionine during, protein biosynthesis. They exist in two isoforms, MetAP1 and MetAP2. The, anti-angiogenic compound fumagillin binds tightly to the Type 2 MetAPs but, only weakly to Type 1. High-affinity complexes of fumagillin and its, relative ovalicin with Type 2 human MetAP have been reported. Here we, describe the crystallographic structure of the low-affinity complex, between ovalicin and Type 1 human MetAP at 1.1 A resolution. This provides, the first opportunity to compare the structures of ovalicin or fumagillin, bound to a Type 1 and a Type 2 MetAP. For both Type 1 and Type 2 human, MetAPs the inhibitor makes a covalent adduct with a corresponding, histidine. At the same time there are significant differences in the, alignment of the inhibitors within the respective active sites. It has, been argued that the lower affinity of ovalicin and fumagillin for the, Type 1 MetAPs is due to the smaller size of their active sites relative to, the Type 2 enzymes. Comparison with the uncomplexed structure of human, Type 1 MetAP indicates that there is some truth to this. Several active, site residues have to move "outward" by 0.5 Angstroms or so to accommodate, the inhibitor. Other residues move "inward." There are, however, other, factors that come into play. In particular, the side chain of His310, rotates by 134 degrees into a different position where (together with, Glu128 and Tyr195) it coordinates a metal ion not seen at this site in the, native enzyme.
About this StructureAbout this Structure
2GZ5 is a Single protein structure of sequence from Homo sapiens with CO, K, OVA and GOL as ligands. Active as Methionyl aminopeptidase, with EC number 3.4.11.18 Full crystallographic information is available from OCA.
ReferenceReference
Structure of the angiogenesis inhibitor ovalicin bound to its noncognate target, human Type 1 methionine aminopeptidase., Addlagatta A, Matthews BW, Protein Sci. 2006 Aug;15(8):1842-8. Epub 2006 Jul 5. PMID:16823043
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