1xr3
From Proteopedia
(New page: 200px<br /><applet load="1xr3" size="450" color="white" frame="true" align="right" spinBox="true" caption="1xr3, resolution 2.71Å" /> '''Actinorhodin Polyket...) |
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| - | [[Image:1xr3.gif|left|200px]]<br /><applet load="1xr3" size=" | + | [[Image:1xr3.gif|left|200px]]<br /><applet load="1xr3" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="1xr3, resolution 2.71Å" /> | caption="1xr3, resolution 2.71Å" /> | ||
'''Actinorhodin Polyketide Ketoreductase with NADP and the Inhibitor Isoniazid bound'''<br /> | '''Actinorhodin Polyketide Ketoreductase with NADP and the Inhibitor Isoniazid bound'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Aromatic polyketides are a class of natural products that include many | + | Aromatic polyketides are a class of natural products that include many pharmaceutically important aromatic compounds. Understanding the structure and function of PKS will provide clues to the molecular basis of polyketide biosynthesis specificity. Polyketide chain reduction by ketoreductase (KR) provides regio- and stereochemical diversity. Two cocrystal structures of actinorhodin polyketide ketoreductase (act KR) were solved to 2.3 A with either the cofactor NADP(+) or NADPH bound. The monomer fold is a highly conserved Rossmann fold. Subtle differences between structures of act KR and fatty acid KRs fine-tune the tetramer interface and substrate binding pocket. Comparisons of the NADP(+)- and NADPH-bound structures indicate that the alpha6-alpha7 loop region is highly flexible. The intricate proton-relay network in the active site leads to the proposed catalytic mechanism involving four waters, NADPH, and the active site tetrad Asn114-Ser144-Tyr157-Lys161. Acyl carrier protein and substrate docking models shed light on the molecular basis of KR regio- and stereoselectivity, as well as the differences between aromatic polyketide and fatty acid biosyntheses. Sequence comparison indicates that the above features are highly conserved among aromatic polyketide KRs. The structures of act KR provide an important step toward understanding aromatic PKS and will enhance our ability to design novel aromatic polyketide natural products with different reduction patterns. |
==About this Structure== | ==About this Structure== | ||
| - | 1XR3 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Streptomyces_coelicolor Streptomyces coelicolor] with NAP and ISZ as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http:// | + | 1XR3 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Streptomyces_coelicolor Streptomyces coelicolor] with <scene name='pdbligand=NAP:'>NAP</scene> and <scene name='pdbligand=ISZ:'>ISZ</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1XR3 OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Streptomyces coelicolor]] | [[Category: Streptomyces coelicolor]] | ||
| - | [[Category: Hill, J | + | [[Category: Hill, J A.]] |
| - | [[Category: Korman, T | + | [[Category: Korman, T P.]] |
| - | [[Category: Tsai, S | + | [[Category: Tsai, S C.]] |
| - | [[Category: Vu, T | + | [[Category: Vu, T N.]] |
[[Category: ISZ]] | [[Category: ISZ]] | ||
[[Category: NAP]] | [[Category: NAP]] | ||
[[Category: protein-inhibitor complex]] | [[Category: protein-inhibitor complex]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 15:57:47 2008'' |
Revision as of 13:57, 21 February 2008
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Actinorhodin Polyketide Ketoreductase with NADP and the Inhibitor Isoniazid bound
Overview
Aromatic polyketides are a class of natural products that include many pharmaceutically important aromatic compounds. Understanding the structure and function of PKS will provide clues to the molecular basis of polyketide biosynthesis specificity. Polyketide chain reduction by ketoreductase (KR) provides regio- and stereochemical diversity. Two cocrystal structures of actinorhodin polyketide ketoreductase (act KR) were solved to 2.3 A with either the cofactor NADP(+) or NADPH bound. The monomer fold is a highly conserved Rossmann fold. Subtle differences between structures of act KR and fatty acid KRs fine-tune the tetramer interface and substrate binding pocket. Comparisons of the NADP(+)- and NADPH-bound structures indicate that the alpha6-alpha7 loop region is highly flexible. The intricate proton-relay network in the active site leads to the proposed catalytic mechanism involving four waters, NADPH, and the active site tetrad Asn114-Ser144-Tyr157-Lys161. Acyl carrier protein and substrate docking models shed light on the molecular basis of KR regio- and stereoselectivity, as well as the differences between aromatic polyketide and fatty acid biosyntheses. Sequence comparison indicates that the above features are highly conserved among aromatic polyketide KRs. The structures of act KR provide an important step toward understanding aromatic PKS and will enhance our ability to design novel aromatic polyketide natural products with different reduction patterns.
About this Structure
1XR3 is a Single protein structure of sequence from Streptomyces coelicolor with and as ligands. Full crystallographic information is available from OCA.
Reference
Structural analysis of actinorhodin polyketide ketoreductase: cofactor binding and substrate specificity., Korman TP, Hill JA, Vu TN, Tsai SC, Biochemistry. 2004 Nov 23;43(46):14529-38. PMID:15544323
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