4FEC: Crystal Structure Of Htt36q3h

Citation:
Abstract
Huntington disease is an autosomal-dominant neurodegenerative disorder caused by a polyglutamine (polyQ) expansion (> 35Q) in the first exon (EX1) of huntingtin protein (Htt). mHtt protein is thought to adopt one or more toxic conformation(s) that are involved in pathogenic interactions in cells . However, the structure of mHtt is not known. Here, we present a near atomic resolution structure of mHtt36Q-EX1. To facilitate crystallization, three histidine residues (3H) were introduced within the Htt36Q stretch resulting in the sequence of Q 7HQHQHQ 27. The Htt36Q3H region adopts alpha-helix, loop, beta-hairpin conformations. Furthermore, we observed interactions between the backbone of the Htt36Q3H beta-strand with the aromatic residues mimicking putative-toxic interactions with other proteins. Our findings support previous predictions that the expanded mHtt-polyQ region adopts a beta-sheet structure. Detailed structural information about mHtt improves our understanding of the pathogenic mechanisms in HD and other polyQ expansion disorders and may form the basis for rational design of small molecules that target toxic conformations of disease-causing proteins.
PDB ID: 4FECDownload
MMDB ID: 108280
PDB Deposition Date: 2012/5/30
Updated in MMDB: 2013/07
Experimental Method:
x-ray diffraction
Resolution: 3  Å
Similar Structures:
Biological Unit for 4FEC: trimeric; determined by author and by software (PISA)
Molecular Components in 4FEC
Label Count Molecule
Proteins (3 molecules)
3
Maltose-binding Periplasmic Protein,huntingtin
Molecule annotation
Chemicals (31 molecules)
1
31
* Click molecule labels to explore molecular sequence information.

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