1mn6: Difference between revisions

Revision as of 14:56, 21 February 2008

Thioesterase Domain from Picromycin Polyketide Synthase, pH 7.6

OverviewOverview

Modular polyketide synthases (PKSs) synthesize the polyketide cores of pharmacologically important natural products such as erythromycin and picromycin. Understanding PKSs at high resolution could present new opportunities for chemoenzymatic synthesis of complex molecules. The crystal structures of macrocycle-forming thioesterase (TE) domains from the picromycin synthase (PICS) and 6-deoxyerythronolide B synthase (DEBS) were determined to 1.8-3.0 A with an R(crys) of 19.2-24.4%, including three structures of PICS TE (crystallized at pH 7.6, 8.0, and 8.4) and a second crystal form of DEBS TE. As predicted by the previous work on DEBS TE [Tsai, S. C., et al. (2001) Proc. Natl. Acad. Sci. U.S.A. 98, 14808-14813], PICS TE contains an open substrate channel and a hydrophobic dimer interface. Notwithstanding their similarity, the dimer interfaces and substrate channels of DEBS TE and PICS TE reveal key differences. The structural basis for the divergent substrate specificities of DEBS TE and PICS TE is analyzed. The size of the substrate channel increases with increasing pH, presumably due to electrostatic repulsion in the channel at elevated pH. Together, these structures support previous predictions that macrocycle-forming thioesterases from PKSs share the same protein fold, an open substrate channel, a similar catalytic mechanism, and a hydrophobic dimer interface. They also provide a basis for the design of enzymes capable of catalyzing regioselective macrocyclization of natural or synthetic substrates. A series of high-resolution snapshots of a protein channel at different pHs is presented alongside analysis of channel residues, which could help in the redesign of the protein channel architecture.

About this StructureAbout this Structure

1MN6 is a Single protein structure of sequence from Streptomyces venezuelae. Full crystallographic information is available from OCA.

ReferenceReference

Insights into channel architecture and substrate specificity from crystal structures of two macrocycle-forming thioesterases of modular polyketide synthases., Tsai SC, Lu H, Cane DE, Khosla C, Stroud RM, Biochemistry. 2002 Oct 22;41(42):12598-606. PMID:12379102

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-[[Image:1mn6.jpg|left|200px]]<br /><applet load="1mn6" size="450" color="white" frame="true" align="right" spinBox="true"
+[[Image:1mn6.jpg|left|200px]]<br /><applet load="1mn6" size="350" color="white" frame="true" align="right" spinBox="true"
 caption="1mn6, resolution 2.20&Aring;" />
 '''Thioesterase Domain from Picromycin Polyketide Synthase, pH 7.6'''<br />
 ==Overview==
-Modular polyketide synthases (PKSs) synthesize the polyketide cores of, pharmacologically important natural products such as erythromycin and, picromycin. Understanding PKSs at high resolution could present new, opportunities for chemoenzymatic synthesis of complex molecules. The, crystal structures of macrocycle-forming thioesterase (TE) domains from, the picromycin synthase (PICS) and 6-deoxyerythronolide B synthase (DEBS), were determined to 1.8-3.0 A with an R(crys) of 19.2-24.4%, including, three structures of PICS TE (crystallized at pH 7.6, 8.0, and 8.4) and a, second crystal form of DEBS TE. As predicted by the previous work on DEBS, TE [Tsai, S. C., et al. (2001) Proc. Natl. Acad. Sci. U.S.A. 98, 14808-14813], PICS TE contains an open substrate channel and a hydrophobic, dimer interface. Notwithstanding their similarity, the dimer interfaces, and substrate channels of DEBS TE and PICS TE reveal key differences. The, structural basis for the divergent substrate specificities of DEBS TE and, PICS TE is analyzed. The size of the substrate channel increases with, increasing pH, presumably due to electrostatic repulsion in the channel at, elevated pH. Together, these structures support previous predictions that, macrocycle-forming thioesterases from PKSs share the same protein fold, an, open substrate channel, a similar catalytic mechanism, and a hydrophobic, dimer interface. They also provide a basis for the design of enzymes, capable of catalyzing regioselective macrocyclization of natural or, synthetic substrates. A series of high-resolution snapshots of a protein, channel at different pHs is presented alongside analysis of channel, residues, which could help in the redesign of the protein channel, architecture.
+Modular polyketide synthases (PKSs) synthesize the polyketide cores of pharmacologically important natural products such as erythromycin and picromycin. Understanding PKSs at high resolution could present new opportunities for chemoenzymatic synthesis of complex molecules. The crystal structures of macrocycle-forming thioesterase (TE) domains from the picromycin synthase (PICS) and 6-deoxyerythronolide B synthase (DEBS) were determined to 1.8-3.0 A with an R(crys) of 19.2-24.4%, including three structures of PICS TE (crystallized at pH 7.6, 8.0, and 8.4) and a second crystal form of DEBS TE. As predicted by the previous work on DEBS TE [Tsai, S. C., et al. (2001) Proc. Natl. Acad. Sci. U.S.A. 98, 14808-14813], PICS TE contains an open substrate channel and a hydrophobic dimer interface. Notwithstanding their similarity, the dimer interfaces and substrate channels of DEBS TE and PICS TE reveal key differences. The structural basis for the divergent substrate specificities of DEBS TE and PICS TE is analyzed. The size of the substrate channel increases with increasing pH, presumably due to electrostatic repulsion in the channel at elevated pH. Together, these structures support previous predictions that macrocycle-forming thioesterases from PKSs share the same protein fold, an open substrate channel, a similar catalytic mechanism, and a hydrophobic dimer interface. They also provide a basis for the design of enzymes capable of catalyzing regioselective macrocyclization of natural or synthetic substrates. A series of high-resolution snapshots of a protein channel at different pHs is presented alongside analysis of channel residues, which could help in the redesign of the protein channel architecture.
 ==About this Structure==
-MN6 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Streptomyces_venezuelae Streptomyces venezuelae]. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1MN6 OCA].
+MN6 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Streptomyces_venezuelae Streptomyces venezuelae]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1MN6 OCA].
 ==Reference==
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 [[Category: Single protein]]
 [[Category: Streptomyces venezuelae]]
-[[Category: Cane, D.E.]]
+[[Category: Cane, D E.]]
 [[Category: Khosla, C.]]
 [[Category: Lu, H.]]
-[[Category: Stroud, R.M.]]
+[[Category: Stroud, R M.]]
-[[Category: Tsai, S.C.]]
+[[Category: Tsai, S C.]]
 [[Category: alpha-beta hydrolase]]
 [[Category: open substrate channel]]
@@ Line 23: / Line 23: @@
 [[Category: thioesterase]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Sun Nov 25 04:22:37 2007''
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