1eoj
From Proteopedia
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| - | [[Image:1eoj.gif|left|200px]] | + | [[Image:1eoj.gif|left|200px]] |
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| - | '''DESIGN OF P1' AND P3' RESIDUES OF TRIVALENT THROMBIN INHIBITORS AND THEIR CRYSTAL STRUCTURES''' | + | {{Structure |
| + | |PDB= 1eoj |SIZE=350|CAPTION= <scene name='initialview01'>1eoj</scene>, resolution 2.1Å | ||
| + | |SITE= | ||
| + | |LIGAND= <scene name='pdbligand=BBS:4-TERT-BUTYLBENZENESULFONIC ACID'>BBS</scene> | ||
| + | |ACTIVITY= [http://en.wikipedia.org/wiki/Thrombin Thrombin], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.5 3.4.21.5] | ||
| + | |GENE= | ||
| + | }} | ||
| + | |||
| + | '''DESIGN OF P1' AND P3' RESIDUES OF TRIVALENT THROMBIN INHIBITORS AND THEIR CRYSTAL STRUCTURES''' | ||
| + | |||
==Overview== | ==Overview== | ||
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==About this Structure== | ==About this Structure== | ||
| - | 1EOJ is a [ | + | 1EOJ is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1EOJ OCA]. |
==Reference== | ==Reference== | ||
| - | Design of P1' and P3' residues of trivalent thrombin inhibitors and their crystal structures., Slon-Usakiewicz JJ, Sivaraman J, Li Y, Cygler M, Konishi Y, Biochemistry. 2000 Mar 7;39(9):2384-91. PMID:[http:// | + | Design of P1' and P3' residues of trivalent thrombin inhibitors and their crystal structures., Slon-Usakiewicz JJ, Sivaraman J, Li Y, Cygler M, Konishi Y, Biochemistry. 2000 Mar 7;39(9):2384-91. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/10694407 10694407] |
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
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[[Category: crystal structure]] | [[Category: crystal structure]] | ||
[[Category: serine protease]] | [[Category: serine protease]] | ||
| - | [[Category: thrombin | + | [[Category: thrombin inhibitor]] |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 10:58:22 2008'' |
Revision as of 08:58, 20 March 2008
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| , resolution 2.1Å | |||||||
|---|---|---|---|---|---|---|---|
| Ligands: | |||||||
| Activity: | Thrombin, with EC number 3.4.21.5 | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
DESIGN OF P1' AND P3' RESIDUES OF TRIVALENT THROMBIN INHIBITORS AND THEIR CRYSTAL STRUCTURES
Contents |
Overview
Synthetic bivalent thrombin inhibitors comprise an active site blocking segment, a fibrinogen recognition exosite blocking segment, and a linker connecting these segments. Possible nonpolar interactions of the P1' and P3' residues of the linker with thrombin S1' and S3' subsites, respectively, were identified using the "Methyl Scan" method [Slon-Usakiewicz et al. (1997) Biochemistry 36, 13494-13502]. A series of inhibitors (4-tert-butylbenzenesulfonyl)-Arg-(D-pipecolic acid)-Xaa-Gly-Yaa-Gly-betaAla-Asp-Tyr-Glu-Pro-Ile-Pro-Glu-Glu-Ala- (be ta-cyclohexylalanine)-(D-Glu)-OH, in which nonpolar P1' residue Xaa or P3' residue Yaa was incorporated, were designed and improved the affinity to thrombin. Substitution of the P3' residue with D-phenylglycine or D-Phe improved the K(i) value to (9.5 +/- 0.6) x 10(-14) or 1.3 +/- 0.5 x 10(-13) M, respectively, compared to that of a reference inhibitor with Gly residues at Xaa and Yaa residues (K(i) = (2.4 +/- 0.5) x 10(-11) M). Similarly, substitution of the P1' residue with L-norleucine or L-beta-(2-thienyl)alanine lowered the K(i) values to (8.2 +/- 0.6) x 10(-14) or (5.1 +/- 0.4) x 10(-14) M, respectively. The linker Gly-Gly-Gly-betaAla of the inhibitors in the previous sentence was simplified with 12-aminododecanoic acid, resulting in further improvement of the K(i) values to (3.8 +/- 0.6) x 10(-14) or (1.7 +/- 0.4) x 10(-14) M, respectively. These K(i) values are equivalent to that of natural hirudin (2.2 x 10(-14) M), yet the size of the synthetic inhibitors (2 kD) is only one-third that of hirudin (7 kD). Two inhibitors, with L-norleucine or L-beta-(2-thienyl)alanine at the P1' residue and the improved linker of 12-aminododecanoic acid, were crystallized in complex with human alpha-thrombin. The crystal structures of these complexes were solved and refined to 2.1 A resolution. The Lys(60F) side chain of thrombin moved significantly and formed a large nonpolar S1' subsite to accommodate the bulky P1' residue.
Disease
Known diseases associated with this structure: Dysprothrombinemia OMIM:[176930], Hyperprothrombinemia OMIM:[176930], Hypoprothrombinemia OMIM:[176930]
About this Structure
1EOJ is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Design of P1' and P3' residues of trivalent thrombin inhibitors and their crystal structures., Slon-Usakiewicz JJ, Sivaraman J, Li Y, Cygler M, Konishi Y, Biochemistry. 2000 Mar 7;39(9):2384-91. PMID:10694407
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