1lk6: Difference between revisions

Revision as of 14:45, 21 February 2008

Structure of dimeric antithrombin complexed with a P14-P9 reactive loop peptide and an exogenous tripeptide

OverviewOverview

Polymerization of serpins commonly results from mutations in the shutter region underlying the bifurcation of strands 3 and 5 of the A-sheet, with entry beyond this point being barred by a H-bond network centered on His-334. Exposure of this histidine in antithrombin, which has a partially opened sheet, allows polymerization and peptide insertion to occur at pH 6 or less when His-334 will be predictably protonated with disruption of the H-bond network. Similarly, thermal stability of antithrombin is pH-dependent with a single unfolding transition at pH 6, but there is no such transition when His-334 is buried by a fully closed A-sheet in heparin-complexed antithrombin or in alpha(1)-antitrypsin. Replacement of His-334 in alpha(1)-antitrypsin by a serine or alanine at pH 7.4 results in the same polymerization and loop-peptide acceptance observed with antithrombin at low pH. The critical role of His-334 and the re-formation of its H-bond network by the conserved P8 threonine, on the full insertion of strand 4, are relevant for the design of therapeutic blocking agents. This is highlighted here by the crystallographic demonstration that glycerol, which at high concentrations blocks polymerization, can replace the P8 threonine and re-form the disrupted H-bond network with His-334.

About this StructureAbout this Structure

1LK6 is a Single protein structure of sequence from Homo sapiens with , , , and as ligands. Full crystallographic information is available from OCA.

ReferenceReference

Serpin polymerization is prevented by a hydrogen bond network that is centered on his-334 and stabilized by glycerol., Zhou A, Stein PE, Huntington JA, Carrell RW, J Biol Chem. 2003 Apr 25;278(17):15116-22. Epub 2003 Feb 10. PMID:12578831

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OCA

@@ Line 4: / Line 4: @@
 ==Overview==
-Polymerization of serpins commonly results from mutations in the shutter, region underlying the bifurcation of strands 3 and 5 of the A-sheet, with, entry beyond this point being barred by a H-bond network centered on, His-334. Exposure of this histidine in antithrombin, which has a partially, opened sheet, allows polymerization and peptide insertion to occur at pH 6, or less when His-334 will be predictably protonated with disruption of the, H-bond network. Similarly, thermal stability of antithrombin is, pH-dependent with a single unfolding transition at pH 6, but there is no, such transition when His-334 is buried by a fully closed A-sheet in, heparin-complexed antithrombin or in alpha(1)-antitrypsin. Replacement of, His-334 in alpha(1)-antitrypsin by a serine or alanine at pH 7.4 results, in the same polymerization and loop-peptide acceptance observed with, antithrombin at low pH. The critical role of His-334 and the re-formation, of its H-bond network by the conserved P8 threonine, on the full insertion, of strand 4, are relevant for the design of therapeutic blocking agents., This is highlighted here by the crystallographic demonstration that, glycerol, which at high concentrations blocks polymerization, can replace, the P8 threonine and re-form the disrupted H-bond network with His-334.
+Polymerization of serpins commonly results from mutations in the shutter region underlying the bifurcation of strands 3 and 5 of the A-sheet, with entry beyond this point being barred by a H-bond network centered on His-334. Exposure of this histidine in antithrombin, which has a partially opened sheet, allows polymerization and peptide insertion to occur at pH 6 or less when His-334 will be predictably protonated with disruption of the H-bond network. Similarly, thermal stability of antithrombin is pH-dependent with a single unfolding transition at pH 6, but there is no such transition when His-334 is buried by a fully closed A-sheet in heparin-complexed antithrombin or in alpha(1)-antitrypsin. Replacement of His-334 in alpha(1)-antitrypsin by a serine or alanine at pH 7.4 results in the same polymerization and loop-peptide acceptance observed with antithrombin at low pH. The critical role of His-334 and the re-formation of its H-bond network by the conserved P8 threonine, on the full insertion of strand 4, are relevant for the design of therapeutic blocking agents. This is highlighted here by the crystallographic demonstration that glycerol, which at high concentrations blocks polymerization, can replace the P8 threonine and re-form the disrupted H-bond network with His-334.
 ==About this Structure==
@@ Line 13: / Line 13: @@
 [[Category: Homo sapiens]]
 [[Category: Single protein]]
-[[Category: Carrell, R.W.]]
+[[Category: Carrell, R W.]]
-[[Category: Huntington, J.A.]]
+[[Category: Huntington, J A.]]
-[[Category: Lomas, D.A.]]
+[[Category: Lomas, D A.]]
-[[Category: Stein, P.E.]]
+[[Category: Stein, P E.]]
 [[Category: Zhou, A.]]
 [[Category: ACE]]
@@ Line 26: / Line 26: @@
 [[Category: loop-sheet polymer]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri Feb 15 16:18:56 2008''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 13:45:47 2008''