2op9

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[[Image:2op9.gif|left|200px]]<br /><applet load="2op9" size="350" color="white" frame="true" align="right" spinBox="true"
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[[Image:2op9.gif|left|200px]]
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caption="2op9, resolution 1.800&Aring;" />
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'''Substrate Specificity Profiling and Identification of a New Class of Inhibitor for the Major Protease of the SARS Coronavirus'''<br />
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{{Structure
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|PDB= 2op9 |SIZE=350|CAPTION= <scene name='initialview01'>2op9</scene>, resolution 1.800&Aring;
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|SITE= <scene name='pdbsite=AC1:Wr1+Binding+Site+For+Residue+A+601'>AC1</scene> and <scene name='pdbsite=AC2:Wr1+Binding+Site+For+Residue+B+602'>AC2</scene>
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|LIGAND= <scene name='pdbligand=WR1:NALPHA-[(BENZYLOXY)CARBONYL]-N-[(1R)-4-HYDROXY-1-METHYL-2-OXOBUTYL]-L-PHENYLALANINAMIDE'>WR1</scene>
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|ACTIVITY=
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|GENE= 3Clpro ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=227859 SARS coronavirus])
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}}
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'''Substrate Specificity Profiling and Identification of a New Class of Inhibitor for the Major Protease of the SARS Coronavirus'''
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==Overview==
==Overview==
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==About this Structure==
==About this Structure==
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2OP9 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Sars_coronavirus Sars coronavirus] with <scene name='pdbligand=WR1:'>WR1</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Known structural/functional Sites: <scene name='pdbsite=AC1:Wr1+Binding+Site+For+Residue+A+601'>AC1</scene> and <scene name='pdbsite=AC2:Wr1+Binding+Site+For+Residue+B+602'>AC2</scene>. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2OP9 OCA].
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2OP9 is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Sars_coronavirus Sars coronavirus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2OP9 OCA].
==Reference==
==Reference==
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Substrate specificity profiling and identification of a new class of inhibitor for the major protease of the SARS coronavirus., Goetz DH, Choe Y, Hansell E, Chen YT, McDowell M, Jonsson CB, Roush WR, McKerrow J, Craik CS, Biochemistry. 2007 Jul 31;46(30):8744-52. Epub 2007 Jul 3. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=17605471 17605471]
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Substrate specificity profiling and identification of a new class of inhibitor for the major protease of the SARS coronavirus., Goetz DH, Choe Y, Hansell E, Chen YT, McDowell M, Jonsson CB, Roush WR, McKerrow J, Craik CS, Biochemistry. 2007 Jul 31;46(30):8744-52. Epub 2007 Jul 3. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/17605471 17605471]
[[Category: Sars coronavirus]]
[[Category: Sars coronavirus]]
[[Category: Single protein]]
[[Category: Single protein]]
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[[Category: protease]]
[[Category: protease]]
[[Category: proteinase]]
[[Category: proteinase]]
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[[Category: sars]]
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[[Category: sar]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 18:21:06 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 18:02:40 2008''

Revision as of 16:02, 20 March 2008

Image:2op9.gif


PDB ID 2op9

Drag the structure with the mouse to rotate
, resolution 1.800Å
Sites: and
Ligands:
Gene: 3Clpro (SARS coronavirus)
Coordinates: save as pdb, mmCIF, xml



Substrate Specificity Profiling and Identification of a New Class of Inhibitor for the Major Protease of the SARS Coronavirus


Overview

Severe acute respiratory syndrome (SARS) is an emerging infectious disease associated with a high rate of mortality. The SARS-associated coronavirus (SARS-CoV) has been identified as the etiological agent of the disease. Although public health procedures have been effective in combating the spread of SARS, concern remains about the possibility of a recurrence. Various approaches are being pursued for the development of efficacious therapeutics. One promising approach is to develop small molecule inhibitors of the essential major polyprotein processing protease 3Clpro. Here we report a complete description of the tetrapeptide substrate specificity of 3Clpro using fully degenerate peptide libraries consisting of all 160,000 possible naturally occurring tetrapeptides. The substrate specificity data show the expected P1-Gln P2-Leu specificity and elucidate a novel preference for P1-His containing substrates equal to the expected preference for P1-Gln. These data were then used to develop optimal substrates for a high-throughput screen of a 2000 compound small-molecule inhibitor library consisting of known cysteine protease inhibitor scaffolds. We also report the 1.8 A X-ray crystal structure of 3Clpro bound to an irreversible inhibitor. This inhibitor, an alpha,beta-epoxyketone, inhibits 3Clpro with a k3/Ki of 0.002 microM(-1) s(-1) in a mode consistent with the substrate specificity data. Finally, we report the successful rational improvement of this scaffold with second generation inhibitors. These data provide the foundation for a rational small-molecule inhibitor design effort based upon the inhibitor scaffold identified, the crystal structure of the complex, and a more complete understanding of P1-P4 substrate specificity.

About this Structure

2OP9 is a Single protein structure of sequence from Sars coronavirus. Full crystallographic information is available from OCA.

Reference

Substrate specificity profiling and identification of a new class of inhibitor for the major protease of the SARS coronavirus., Goetz DH, Choe Y, Hansell E, Chen YT, McDowell M, Jonsson CB, Roush WR, McKerrow J, Craik CS, Biochemistry. 2007 Jul 31;46(30):8744-52. Epub 2007 Jul 3. PMID:17605471

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