3fgq

Crystal structure of native human neuroserpin

spinqualitylabelsall models 3fgq, resolution 2.09Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3fgq is a 2 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 2.09Å Ligands: GOL Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease NEUS_HUMAN Familial encephalopathy with neuroserpin inclusion bodies. The disease is caused by mutations affecting the gene represented in this entry. Function NEUS_HUMAN Serine protease inhibitor that inhibits plasminogen activators and plasmin but not thrombin. May be involved in the formation or reorganization of synaptic connections as well as for synaptic plasticity in the adult nervous system. May protect neurons from cell damage by tissue-type plasminogen activator. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMed Neuroserpin is a selective inhibitor of tissue-type plasminogen activator (tPA) that plays an important role in neuronal plasticity, memory, and learning. We report here the crystal structure of native human neuroserpin at 2.1 A resolution. The structure has a helical reactive center loop and an omega loop between strands 1B and 2B. The omega loop contributes to the inhibition of tPA, as deletion of this motif reduced the association rate constant with tPA by threefold but had no effect on the kinetics of interaction with urokinase. Point mutations in neuroserpin cause the formation of ordered intracellular polymers that underlie dementia familial encephalopathy with neuroserpin inclusion bodies (FENIB). Wild-type neuroserpin is also unstable and readily forms polymers under near-physiological conditions in vitro. This is, in part, due to the substitution of a conserved alanine for serine at position 340. The replacement of Ser340 by Ala increased the melting temperature by 3 degrees C and reduced polymerization as compared to wild-type neuroserpin. Similarly, neuroserpin has Asn-Leu-Val at the end of helix F and thus differs markedly from the Gly-X-Ile consensus sequence of the serpins. Restoration of these amino acids to the consensus sequence increased thermal stability and reduced the polymerization of neuroserpin and its transition to the latent conformer. Moreover, introduction of the consensus sequence into S49P neuroserpin that causes FENIB increased the stability and inhibitory activity of the mutant, as well as blocked polymerization and increased the yield of protein during refolding. These data provide a molecular explanation for the inherent instability of neuroserpin and the effect of point mutations that underlie the dementia FENIB. The 2.1-A crystal structure of native neuroserpin reveals unique structural elements that contribute to conformational instability.,Takehara S, Onda M, Zhang J, Nishiyama M, Yang X, Mikami B, Lomas DA J Mol Biol. 2009 Apr 24;388(1):11-20. Epub 2009 Mar 10. PMID:19285087 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Serpin 3D structures

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