1JVQ: Crystal Structure At 2.6a Of The Ternary Complex Between Antithrombin, A P14-P8 Reactive Loop Peptide, And An Exogenous Tetrapeptide

Citation:
Abstract
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.
PDB ID: 1JVQDownload
MMDB ID: 103636
PDB Deposition Date: 2001/8/31
Updated in MMDB: 2012/10
Experimental Method:
x-ray diffraction
Resolution: 2.6  Å
Source Organism:
synthetic construct
Similar Structures:
Biological Unit for 1JVQ: tetrameric; determined by author and by software (PISA)
Molecular Components in 1JVQ
Label Count Molecule
Proteins (4 molecules)
2
Antithrombin-iii(Gene symbol: SERPINC1)
Molecule annotation
1
P14-p8 Reactive Loop Peptide
Molecule annotation
1
Exogenous Cholecystokinin Tetrapeptide
Molecule annotation
Chemicals (9 molecules)
1
7
2
2
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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