1rgq: Difference between revisions
New page: left|200px<br /><applet load="1rgq" size="450" color="white" frame="true" align="right" spinBox="true" caption="1rgq, resolution 2.90Å" /> '''M9A HCV Protease com... |
No edit summary |
||
| Line 1: | Line 1: | ||
[[Image:1rgq.gif|left|200px]]<br /><applet load="1rgq" size=" | [[Image:1rgq.gif|left|200px]]<br /><applet load="1rgq" size="350" color="white" frame="true" align="right" spinBox="true" | ||
caption="1rgq, resolution 2.90Å" /> | caption="1rgq, resolution 2.90Å" /> | ||
'''M9A HCV Protease complex with pentapeptide keto-amide inhibitor'''<br /> | '''M9A HCV Protease complex with pentapeptide keto-amide inhibitor'''<br /> | ||
==Overview== | ==Overview== | ||
A series of novel peptidyl-alpha-ketoamide compounds were evaluated as | A series of novel peptidyl-alpha-ketoamide compounds were evaluated as inhibitors of the deltaNS3-NS4A serine protease from the hepatitis C virus. These peptidyl-alpha-ketoamide inhibitors with Ki values ranging from 0.17 nM to 5.6 microM exhibited slow-binding inhibition. Kinetic studies established one-step kinetic mechanisms and dissociation rate constants in the 3-7 x 10(-5) s(-1) range for these compounds. The association rate constants, which ranged from 10 to 263,000 M(-1) s(-1), were responsible for the greater than four order of magnitude overall binding affinity range exhibited by this series. An X-ray crystal structure of a protease-inhibitor complex revealed an unusual interaction between the oxyanion of the adduct and the protein as well as a significant movement in the S1' region of the protein loop comprising residues 35-42. These results are quite different from peptidyl-alpha-ketoacid inhibition of HCV protease, which reportedly undergoes no notable conformational changes and proceeds with a two-step slow-binding kinetic mechanism. | ||
==About this Structure== | ==About this Structure== | ||
1RGQ is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Hepatitis_c_virus Hepatitis c virus] with ZN and AKP as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Hepacivirin Hepacivirin], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.98 3.4.21.98] Full crystallographic information is available from [http:// | 1RGQ is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Hepatitis_c_virus Hepatitis c virus] with <scene name='pdbligand=ZN:'>ZN</scene> and <scene name='pdbligand=AKP:'>AKP</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Hepacivirin Hepacivirin], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.98 3.4.21.98] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1RGQ OCA]. | ||
==Reference== | ==Reference== | ||
| Line 14: | Line 14: | ||
[[Category: Hepatitis c virus]] | [[Category: Hepatitis c virus]] | ||
[[Category: Protein complex]] | [[Category: Protein complex]] | ||
[[Category: Kati, W | [[Category: Kati, W M.]] | ||
[[Category: Klaus, J | [[Category: Klaus, J L.]] | ||
[[Category: Kohlbrenner, W.]] | [[Category: Kohlbrenner, W.]] | ||
[[Category: Liu, Y.]] | [[Category: Liu, Y.]] | ||
[[Category: Molla, A.]] | [[Category: Molla, A.]] | ||
[[Category: Richardson, P | [[Category: Richardson, P L.]] | ||
[[Category: Saldivar, A.]] | [[Category: Saldivar, A.]] | ||
[[Category: Stoll, V | [[Category: Stoll, V S.]] | ||
[[Category: AKP]] | [[Category: AKP]] | ||
[[Category: ZN]] | [[Category: ZN]] | ||
[[Category: hepatitis c virus protease keto amide peptide inhibitor]] | [[Category: hepatitis c virus protease keto amide peptide inhibitor]] | ||
''Page seeded by [http:// | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:50:43 2008'' | ||
Revision as of 15:50, 21 February 2008
|
M9A HCV Protease complex with pentapeptide keto-amide inhibitor
OverviewOverview
A series of novel peptidyl-alpha-ketoamide compounds were evaluated as inhibitors of the deltaNS3-NS4A serine protease from the hepatitis C virus. These peptidyl-alpha-ketoamide inhibitors with Ki values ranging from 0.17 nM to 5.6 microM exhibited slow-binding inhibition. Kinetic studies established one-step kinetic mechanisms and dissociation rate constants in the 3-7 x 10(-5) s(-1) range for these compounds. The association rate constants, which ranged from 10 to 263,000 M(-1) s(-1), were responsible for the greater than four order of magnitude overall binding affinity range exhibited by this series. An X-ray crystal structure of a protease-inhibitor complex revealed an unusual interaction between the oxyanion of the adduct and the protein as well as a significant movement in the S1' region of the protein loop comprising residues 35-42. These results are quite different from peptidyl-alpha-ketoacid inhibition of HCV protease, which reportedly undergoes no notable conformational changes and proceeds with a two-step slow-binding kinetic mechanism.
About this StructureAbout this Structure
1RGQ is a Protein complex structure of sequences from Hepatitis c virus with and as ligands. Active as Hepacivirin, with EC number 3.4.21.98 Full crystallographic information is available from OCA.
ReferenceReference
Hepatitis C NS3 protease inhibition by peptidyl-alpha-ketoamide inhibitors: kinetic mechanism and structure., Liu Y, Stoll VS, Richardson PL, Saldivar A, Klaus JL, Molla A, Kohlbrenner W, Kati WM, Arch Biochem Biophys. 2004 Jan 15;421(2):207-16. PMID:14984200
Page seeded by OCA on Thu Feb 21 14:50:43 2008