1qur: Difference between revisions

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[[Image:1qur.gif|left|200px]]<br />

[[Image:1qur.gif|left|200px]]<br /><applet load="1qur" size="350" color="white" frame="true" align="right" spinBox="true"

<applet load="1qur" size="~~450~~" color="white" frame="true" align="right" spinBox="true"

caption="1qur, resolution 2.0Å" />

'''HUMAN ALPHA-THROMBIN IN COMPLEX WITH BIVALENT, BENZAMIDINE-BASED SYNTHETIC INHIBITOR'''<br />

==Overview==

Two bivalent thrombin inhibitors were synthesized, which consist of a, benzamidine-based active-site-blocking segment, a fibrinogen recognition, exosite inhibitor and a peptidic linker connecting these fragments. BZA-1, hirulog contains an Nalpha-(2-naphthylsulfonyl)-S-3-amidinophenylalanyl-is, onipecotic acid residue connected via the carboxyl group to the linker, segment. The active-site-directed moiety of BZA-2 hirulog, [Nalpha-(2-naphthylsulfonyl-glutamyl)-R-4-amidinophenylal anyl-piperid, ide] was coupled to the linker via the side chain of the glutamic acid., Both BZA-hirulogs contain almost identical linker-exo site inhibitor, parts, except for the substitution of a glycine as the first linker, residue in BZA-1 hirulog by a gamma-amino butyric acid in BZA-2 hirulog, thus increasing flexibility and linker length by two additional atoms., BZA-1 hirulog showed moderate potency (Ki = 0. 50 +/- 0.14 nM), while, BZA-2 hirulog was characterized as a slow, tight binding inhibitor of, thrombin (Ki = 0.29 +/- 0.08 pM). The stability in human plasma of both, analogs was strongly improved compared with hirulog-1. For BZA-2 hirulog a, significantly reduced plasma clearance was observed after intravenous, injection in rats compared with BZA-1 hirulog and hirulog-1. The X-ray, structure of the BZA-2 hirulog in complex with human alpha-thrombin was, solved and confirmed the expected bivalent binding mode.

Two bivalent thrombin inhibitors were synthesized, which consist of a benzamidine-based active-site-blocking segment, a fibrinogen recognition exosite inhibitor and a peptidic linker connecting these fragments. BZA-1 hirulog contains an Nalpha-(2-naphthylsulfonyl)-S-3-amidinophenylalanyl-is onipecotic acid residue connected via the carboxyl group to the linker segment. The active-site-directed moiety of BZA-2 hirulog [Nalpha-(2-naphthylsulfonyl-glutamyl)-R-4-amidinophenylal anyl-piperid ide] was coupled to the linker via the side chain of the glutamic acid. Both BZA-hirulogs contain almost identical linker-exo site inhibitor parts, except for the substitution of a glycine as the first linker residue in BZA-1 hirulog by a gamma-amino butyric acid in BZA-2 hirulog, thus increasing flexibility and linker length by two additional atoms. BZA-1 hirulog showed moderate potency (Ki = 0. 50 +/- 0.14 nM), while BZA-2 hirulog was characterized as a slow, tight binding inhibitor of thrombin (Ki = 0.29 +/- 0.08 pM). The stability in human plasma of both analogs was strongly improved compared with hirulog-1. For BZA-2 hirulog a significantly reduced plasma clearance was observed after intravenous injection in rats compared with BZA-1 hirulog and hirulog-1. The X-ray structure of the BZA-2 hirulog in complex with human alpha-thrombin was solved and confirmed the expected bivalent binding mode.

==Disease==

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==About this Structure==

1QUR is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with NAS, GLU, APH and PIP as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://~~ispc~~.weizmann.ac.il/oca-bin/ocashort?id=1QUR OCA].

1QUR is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=NAS:'>NAS</scene>, <scene name='pdbligand=GLU:'>GLU</scene>, <scene name='pdbligand=APH:'>APH</scene> and <scene name='pdbligand=PIP:'>PIP</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1QUR OCA].

==Reference==

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[[Category: trypsin like serine protease]]

''Page seeded by [http://~~ispc~~.weizmann.ac.il/oca OCA ] on ~~Mon Nov 12 18~~:56:~~48 2007~~''

''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:43:54 2008''

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@@ Line 1: / Line 1: @@
-[[Image:1qur.gif|left|200px]]<br />
+[[Image:1qur.gif|left|200px]]<br /><applet load="1qur" size="350" color="white" frame="true" align="right" spinBox="true"
-<applet load="1qur" size="450" color="white" frame="true" align="right" spinBox="true"
 caption="1qur, resolution 2.0&Aring;" />
 '''HUMAN ALPHA-THROMBIN IN COMPLEX WITH BIVALENT, BENZAMIDINE-BASED SYNTHETIC INHIBITOR'''<br />
 ==Overview==
-Two bivalent thrombin inhibitors were synthesized, which consist of a, benzamidine-based active-site-blocking segment, a fibrinogen recognition, exosite inhibitor and a peptidic linker connecting these fragments. BZA-1, hirulog contains an Nalpha-(2-naphthylsulfonyl)-S-3-amidinophenylalanyl-is, onipecotic acid residue connected via the carboxyl group to the linker, segment. The active-site-directed moiety of BZA-2 hirulog, [Nalpha-(2-naphthylsulfonyl-glutamyl)-R-4-amidinophenylal anyl-piperid, ide] was coupled to the linker via the side chain of the glutamic acid., Both BZA-hirulogs contain almost identical linker-exo site inhibitor, parts, except for the substitution of a glycine as the first linker, residue in BZA-1 hirulog by a gamma-amino butyric acid in BZA-2 hirulog, thus increasing flexibility and linker length by two additional atoms., BZA-1 hirulog showed moderate potency (Ki = 0. 50 +/- 0.14 nM), while, BZA-2 hirulog was characterized as a slow, tight binding inhibitor of, thrombin (Ki = 0.29 +/- 0.08 pM). The stability in human plasma of both, analogs was strongly improved compared with hirulog-1. For BZA-2 hirulog a, significantly reduced plasma clearance was observed after intravenous, injection in rats compared with BZA-1 hirulog and hirulog-1. The X-ray, structure of the BZA-2 hirulog in complex with human alpha-thrombin was, solved and confirmed the expected bivalent binding mode.
+Two bivalent thrombin inhibitors were synthesized, which consist of a benzamidine-based active-site-blocking segment, a fibrinogen recognition exosite inhibitor and a peptidic linker connecting these fragments. BZA-1 hirulog contains an Nalpha-(2-naphthylsulfonyl)-S-3-amidinophenylalanyl-is onipecotic acid residue connected via the carboxyl group to the linker segment. The active-site-directed moiety of BZA-2 hirulog [Nalpha-(2-naphthylsulfonyl-glutamyl)-R-4-amidinophenylal anyl-piperid ide] was coupled to the linker via the side chain of the glutamic acid. Both BZA-hirulogs contain almost identical linker-exo site inhibitor parts, except for the substitution of a glycine as the first linker residue in BZA-1 hirulog by a gamma-amino butyric acid in BZA-2 hirulog, thus increasing flexibility and linker length by two additional atoms. BZA-1 hirulog showed moderate potency (Ki = 0. 50 +/- 0.14 nM), while BZA-2 hirulog was characterized as a slow, tight binding inhibitor of thrombin (Ki = 0.29 +/- 0.08 pM). The stability in human plasma of both analogs was strongly improved compared with hirulog-1. For BZA-2 hirulog a significantly reduced plasma clearance was observed after intravenous injection in rats compared with BZA-1 hirulog and hirulog-1. The X-ray structure of the BZA-2 hirulog in complex with human alpha-thrombin was solved and confirmed the expected bivalent binding mode.
 ==Disease==
@@ Line 11: / Line 10: @@
 ==About this Structure==
-QUR is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with NAS, GLU, APH and PIP as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1QUR OCA].
+QUR is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=NAS:'>NAS</scene>, <scene name='pdbligand=GLU:'>GLU</scene>, <scene name='pdbligand=APH:'>APH</scene> and <scene name='pdbligand=PIP:'>PIP</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1QUR OCA].
 ==Reference==
@@ Line 26: / Line 25: @@
 [[Category: trypsin like serine protease]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 18:56:48 2007''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:43:54 2008''