4rav | pdb_00004rav

Crystal structure of scFvC4 in complex with the first 17 AA of huntingtin

spinqualitylabelsall models 4rav, resolution 2.50Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4rav is a 6 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: SO4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease [HD_HUMAN] Juvenile Huntington disease;Huntington disease. The disease is caused by mutations affecting the gene represented in this entry. Function [HD_HUMAN] May play a role in microtubule-mediated transport or vesicle function. Publication Abstract from PubMed Huntington's disease is triggered by misfolding of fragments of mutant forms of the huntingtin protein (mHTT) with aberrant polyglutamine expansions. The C4 single-chain Fv antibody (scFv) binds to the first 17 residues of huntingtin [HTT(1-17)] and generates substantial protection against multiple phenotypic pathologies in situ and in vivo. We show in this paper that C4 scFv inhibits amyloid formation by exon1 fragments of huntingtin in vitro and elucidate the structural basis for this inhibition and protection by determining the crystal structure of the complex of C4 scFv and HTT(1-17). The peptide binds with residues 3-11 forming an amphipathic helix that makes contact with the antibody fragment in such a way that the hydrophobic face of this helix is shielded from the solvent. Residues 12-17 of the peptide are in an extended conformation and interact with the same region of another C4 scFv:HTT(1-17) complex in the asymmetric unit, resulting in a beta-sheet interface within a dimeric C4 scFv:HTT(1-17) complex. The nature of this scFv-peptide complex was further explored in solution by high-resolution NMR and physicochemical analysis of species in solution. The results provide insights into the manner in which C4 scFv inhibits the aggregation of HTT, and hence into its therapeutic potential, and suggests a structural basis for the initial interactions that underlie the formation of disease-associated amyloid fibrils by HTT. Structure of a single-chain Fv bound to the 17 N-terminal residues of huntingtin provides insights into pathogenic amyloid formation and suppression.,De Genst E, Chirgadze DY, Klein FA, Butler DC, Matak-Vinkovic D, Trottier Y, Huston JS, Messer A, Dobson CM J Mol Biol. 2015 Jun 19;427(12):2166-78. doi: 10.1016/j.jmb.2015.03.021. Epub, 2015 Apr 8. PMID:25861763 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Huntingtin

Proteopedia Page Contributors and Editors (what is this?)

OCA