1eku

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Revision as of 14:37, 12 November 2007

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spinqualitylabelsall models 1eku, resolution 2.9Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

CRYSTAL STRUCTURE OF A BIOLOGICALLY ACTIVE SINGLE CHAIN MUTANT OF HUMAN IFN-GAMMA

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

Overview

A mutant form of human interferon-gamma (IFN-gamma SC1) that binds one, IFN-gamma receptor alpha chain (IFN-gamma R alpha) has been designed and, characterized. IFN-gamma SC1 was derived by linking the two peptide chains, of the IFN-gamma dimer by a seven-residue linker and changing His111 in, the first chain to an aspartic acid residue. Isothermal titration, calorimetry shows that IFN-gamma SC1 forms a 1:1 complex with its, high-affinity receptor (IFN-gamma R alpha) with an affinity of 27(+/- 9), nM. The crystal structure of IFN-gamma SC1 has been determined at 2.9 A, resolution from crystals grown in 1.4 M citrate solutions at pH 7.6., Comparison of the wild-type receptor-binding domain and the, Asp111-containing domain of IFN-gamma SC1 show that they are structurally, equivalent but have very different electrostatic surface potentials. As a, result, surface charge rather than structural changes is likely, responsible for the inability of the His111-->Asp domain of to bind, IFN-gamma R alpha. The AB loops of IFN-gamma SC1 adopt conformations, similar to the ordered loops of IFN-gamma observed in the crystal, structure of the IFN-gamma/IFN-gamma R alpha complex. Thus, IFN-gamma R, alpha binding does not result in a large conformational change in the AB, loop as previously suggested. The structure also reveals the final six, C-terminal amino acid residues of IFN-gamma SC1 (residues 253-258) that, have not been observed in any other reported IFN-gamma structures. Despite, binding to only one IFN-gamma R alpha, IFN-gamma SC1 is biologically, active in cell proliferation, MHC class I induction, and anti-viral, assays. This suggests that one domain of IFN-gamma is sufficient to, recruit IFN-gamma R alpha and IFN-gamma R beta into a complex competent, for eliciting biological activity. The current data are consistent with, the main role of the IFN-gamma dimer being to decrease the dissociation, constant of IFN-gamma for its cellular receptors.

Disease

Known diseases associated with this structure: AIDS, rapid progression to OMIM:[147570], Aplastic anemia OMIM:[147570], Hepatitis C virus, resistance to OMIM:[147570], Interferon, immune, deficiency OMIM:[147570], TSC2 angiomyolipomas, renal, modifier of OMIM:[147570], Tuberculosis, susceptibility to OMIM:[147570]

About this Structure

1EKU is a Single protein structure of sequence from Homo sapiens with SO4 as ligand. Full crystallographic information is available from OCA.

Reference

Design, characterization, and structure of a biologically active single-chain mutant of human IFN-gamma., Landar A, Curry B, Parker MH, DiGiacomo R, Indelicato SR, Nagabhushan TL, Rizzi G, Walter MR, J Mol Biol. 2000 May 26;299(1):169-79. PMID:10860730

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