1eq2: Difference between revisions

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THE CRYSTAL STRUCTURE OF ADP-L-GLYCERO-D-MANNOHEPTOSE 6-EPIMERASE

OverviewOverview

BACKGROUND: ADP-L-glycero--mannoheptose 6-epimerase (AGME) is required for lipopolysaccharide (LPS) biosynthesis in most genera of pathogenic and non-pathogenic Gram-negative bacteria. It catalyzes the interconversion of ADP-D-glycero-D-mannoheptose and ADP-L-glycero-D-mannoheptose, a precursor of the seven-carbon sugar L-glycero-mannoheptose (heptose). Heptose is an obligatory component of the LPS core domain; its absence results in a truncated LPS structure resulting in susceptibility to hydrophobic antibiotics. Heptose is not found in mammalian cells, thus its biosynthetic pathway in bacteria presents a unique target for the design of novel antimicrobial agents. RESULTS: The structure of AGME, in complex with NADP and the catalytic inhibitor ADP-glucose, has been determined at 2.0 A resolution by multiwavelength anomalous diffraction (MAD) phasing methods. AGME is a homopentameric enzyme, which crystallizes with two pentamers in the asymmetric unit. The location of 70 crystallographically independent selenium sites was a key step in the structure determination process. Each monomer comprises two domains: a large N-terminal domain, consisting of a modified seven-stranded Rossmann fold that is associated with NADP binding; and a smaller alpha/beta C-terminal domain involved in substrate binding. CONCLUSIONS: The first structure of an LPS core biosynthetic enzyme leads to an understanding of the mechanism of the conversion between ADP-D-glycero--mannoheptose and ADP-L-glycero-D-mannoheptose. On the basis of its high structural similarity to UDP-galactose epimerase and the three-dimensional positions of the conserved residues Ser116, Tyr140 and Lys144, AGME was classified as a member of the short-chain dehydrogenase/reductase (SDR) superfamily. This study should prove useful in the design of mechanistic and structure-based inhibitors of the AGME catalyzed reaction.

About this StructureAbout this Structure

1EQ2 is a Single protein structure of sequence from Escherichia coli with and as ligands. Active as ADP-glyceromanno-heptose 6-epimerase, with EC number 5.1.3.20 Full crystallographic information is available from OCA.

ReferenceReference

The crystal structure of ADP-L-glycero-D-mannoheptose 6-epimerase: catalysis with a twist., Deacon AM, Ni YS, Coleman WG Jr, Ealick SE, Structure. 2000 May 15;8(5):453-62. PMID:10896473

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-[[Image:1eq2.gif|left|200px]]<br /><applet load="1eq2" size="450" color="white" frame="true" align="right" spinBox="true"
+[[Image:1eq2.gif|left|200px]]<br /><applet load="1eq2" size="350" color="white" frame="true" align="right" spinBox="true"
 caption="1eq2, resolution 2.0&Aring;" />
 '''THE CRYSTAL STRUCTURE OF ADP-L-GLYCERO-D-MANNOHEPTOSE 6-EPIMERASE'''<br />
 ==Overview==
-BACKGROUND: ADP-L-glycero--mannoheptose 6-epimerase (AGME) is required for, lipopolysaccharide (LPS) biosynthesis in most genera of pathogenic and, non-pathogenic Gram-negative bacteria. It catalyzes the interconversion of, ADP-D-glycero-D-mannoheptose and ADP-L-glycero-D-mannoheptose, a precursor, of the seven-carbon sugar L-glycero-mannoheptose (heptose). Heptose is an, obligatory component of the LPS core domain; its absence results in a, truncated LPS structure resulting in susceptibility to hydrophobic, antibiotics. Heptose is not found in mammalian cells, thus its, biosynthetic pathway in bacteria presents a unique target for the design, of novel antimicrobial agents. RESULTS: The structure of AGME, in complex, with NADP and the catalytic inhibitor ADP-glucose, has been determined at, 2.0 A resolution by multiwavelength anomalous diffraction (MAD) phasing, methods. AGME is a homopentameric enzyme, which crystallizes with two, pentamers in the asymmetric unit. The location of 70 crystallographically, independent selenium sites was a key step in the structure determination, process. Each monomer comprises two domains: a large N-terminal domain, consisting of a modified seven-stranded Rossmann fold that is associated, with NADP binding; and a smaller alpha/beta C-terminal domain involved in, substrate binding. CONCLUSIONS: The first structure of an LPS core, biosynthetic enzyme leads to an understanding of the mechanism of the, conversion between ADP-D-glycero--mannoheptose and, ADP-L-glycero-D-mannoheptose. On the basis of its high structural, similarity to UDP-galactose epimerase and the three-dimensional positions, of the conserved residues Ser116, Tyr140 and Lys144, AGME was classified, as a member of the short-chain dehydrogenase/reductase (SDR) superfamily., This study should prove useful in the design of mechanistic and, structure-based inhibitors of the AGME catalyzed reaction.
+BACKGROUND: ADP-L-glycero--mannoheptose 6-epimerase (AGME) is required for lipopolysaccharide (LPS) biosynthesis in most genera of pathogenic and non-pathogenic Gram-negative bacteria. It catalyzes the interconversion of ADP-D-glycero-D-mannoheptose and ADP-L-glycero-D-mannoheptose, a precursor of the seven-carbon sugar L-glycero-mannoheptose (heptose). Heptose is an obligatory component of the LPS core domain; its absence results in a truncated LPS structure resulting in susceptibility to hydrophobic antibiotics. Heptose is not found in mammalian cells, thus its biosynthetic pathway in bacteria presents a unique target for the design of novel antimicrobial agents. RESULTS: The structure of AGME, in complex with NADP and the catalytic inhibitor ADP-glucose, has been determined at 2.0 A resolution by multiwavelength anomalous diffraction (MAD) phasing methods. AGME is a homopentameric enzyme, which crystallizes with two pentamers in the asymmetric unit. The location of 70 crystallographically independent selenium sites was a key step in the structure determination process. Each monomer comprises two domains: a large N-terminal domain, consisting of a modified seven-stranded Rossmann fold that is associated with NADP binding; and a smaller alpha/beta C-terminal domain involved in substrate binding. CONCLUSIONS: The first structure of an LPS core biosynthetic enzyme leads to an understanding of the mechanism of the conversion between ADP-D-glycero--mannoheptose and ADP-L-glycero-D-mannoheptose. On the basis of its high structural similarity to UDP-galactose epimerase and the three-dimensional positions of the conserved residues Ser116, Tyr140 and Lys144, AGME was classified as a member of the short-chain dehydrogenase/reductase (SDR) superfamily. This study should prove useful in the design of mechanistic and structure-based inhibitors of the AGME catalyzed reaction.
 ==About this Structure==
-EQ2 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli] with NAP and ADQ as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/ADP-glyceromanno-heptose_6-epimerase ADP-glyceromanno-heptose 6-epimerase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=5.1.3.20 5.1.3.20] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1EQ2 OCA].
+EQ2 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli] with <scene name='pdbligand=NAP:'>NAP</scene> and <scene name='pdbligand=ADQ:'>ADQ</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/ADP-glyceromanno-heptose_6-epimerase ADP-glyceromanno-heptose 6-epimerase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=5.1.3.20 5.1.3.20] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1EQ2 OCA].
 ==Reference==
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 [[Category: Escherichia coli]]
 [[Category: Single protein]]
-[[Category: Deacon, A.M.]]
+[[Category: Deacon, A M.]]
-[[Category: Ealick, S.E.]]
+[[Category: Ealick, S E.]]
-[[Category: Jr., W.G.Coleman.]]
+[[Category: Jr., W G.Coleman.]]
-[[Category: Ni, Y.S.]]
+[[Category: Ni, Y S.]]
 [[Category: ADQ]]
 [[Category: NAP]]
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 [[Category: short-chain dehydrogenase/reductase fold]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Tue Nov 20 14:13:14 2007''
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