1jvq

From Proteopedia

---

Revision as of 15:38, 12 November 2007

proteopedia linkproteopedia link

spinqualitylabelsall models 1jvq, resolution 2.60Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Crystal structure at 2.6A of the ternary complex between antithrombin, a P14-P8 reactive loop peptide, and an exogenous tetrapeptide

Overview

Many of the late-onset dementias, including Alzheimer's disease and the, prion encephalopathies, arise from the aberrant aggregation of individual, proteins. The serpin family of serine protease inhibitors provides a, well-defined structural example of such pathological aggregation, as its, mutant variants readily form long-chain polymers, resulting in diseases, ranging from thrombosis to dementia. The intermolecular linkages result, from the insertion of the reactive site loop of one serpin molecule into, the middle strand (s4A) position of the A beta-sheet of another molecule., We define here the structural requirements for small peptides to, competitively bind to and block the s4A position to prevent this, intermolecular linkage and polymerisation. The entry and anchoring of, blocking-peptides is facilitated by the presence of a threonine which, inserts into the site equivalent to P8 of s4A. But the critical, requirement for small blocking-peptides is demonstrated in, crystallographic structures of the complexes formed with selected tri- and, tetrapeptides. These structures indicate that the binding is primarily due, to the insertion of peptide hydrophobic side-chains into the P4 and P6, sites of s4A. The findings allow the rational design of synthetic, blocking-peptides small enough to be suitable for mimetic design. This is, demonstrated here with a tetrapeptide that preferentially blocks the, polymerisation of a pathologically unstable serpin commonly present in, people of European descent.

About this Structure

1JVQ is a Single protein structure of sequence from Homo sapiens with NDG, NAG, ACE and NH2 as ligands. Full crystallographic information is available from OCA.

Reference

How small peptides block and reverse serpin polymerisation., Zhou A, Stein PE, Huntington JA, Sivasothy P, Lomas DA, Carrell RW, J Mol Biol. 2004 Sep 17;342(3):931-41. PMID:15342247

Page seeded by OCA on Mon Nov 12 17:45:00 2007