1hzp
From Proteopedia
(New page: 200px<br /><applet load="1hzp" size="450" color="white" frame="true" align="right" spinBox="true" caption="1hzp, resolution 2.10Å" /> '''Crystal Structure of...) |
|||
| Line 1: | Line 1: | ||
| - | [[Image:1hzp.gif|left|200px]]<br /><applet load="1hzp" size=" | + | [[Image:1hzp.gif|left|200px]]<br /><applet load="1hzp" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="1hzp, resolution 2.10Å" /> | caption="1hzp, resolution 2.10Å" /> | ||
'''Crystal Structure of the Myobacterium Tuberculosis Beta-Ketoacyl-Acyl Carrier Protein Synthase III'''<br /> | '''Crystal Structure of the Myobacterium Tuberculosis Beta-Ketoacyl-Acyl Carrier Protein Synthase III'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Mycolic acids (alpha-alkyl-beta-hydroxy long chain fatty acids) cover the | + | Mycolic acids (alpha-alkyl-beta-hydroxy long chain fatty acids) cover the surface of mycobacteria, and inhibition of their biosynthesis is an established mechanism of action for several key front-line anti-tuberculosis drugs. In mycobacteria, long chain acyl-CoA products (C(14)-C(26)) generated by a type I fatty-acid synthase can be used directly for the alpha-branch of mycolic acid or can be extended by a type II fatty-acid synthase to make the meromycolic acid (C(50)-C(56)))-derived component. An unusual Mycobacterium tuberculosis beta-ketoacyl-acyl carrier protein (ACP) synthase III (mtFabH) has been identified, purified, and shown to catalyze a Claisen-type condensation between long chain acyl-CoA substrates such as myristoyl-CoA (C(14)) and malonyl-ACP. This enzyme, presumed to play a key role in initiating meromycolic acid biosynthesis, was crystallized, and its structure was determined at 2.1-A resolution. The mtFabH homodimer is closely similar in topology and active-site structure to Escherichia coli FabH (ecFabH), with a CoA/malonyl-ACP-binding channel leading from the enzyme surface to the buried active-site cysteine residue. Unlike ecFabH, mtFabH contains a second hydrophobic channel leading from the active site. In the ecFabH structure, this channel is blocked by a phenylalanine residue, which constrains specificity to acetyl-CoA, whereas in mtFabH, this residue is a threonine, which permits binding of longer acyl chains. This same channel in mtFabH is capped by an alpha-helix formed adjacent to a 4-amino acid sequence insertion, which limits bound acyl chain length to 16 carbons. These observations offer a molecular basis for understanding the unusual substrate specificity of mtFabH and its probable role in regulating the biosynthesis of the two different length acyl chains required for generation of mycolic acids. This mtFabH presents a new target for structure-based design of novel antimycobacterial agents. |
==About this Structure== | ==About this Structure== | ||
| - | 1HZP is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Mycobacterium_tuberculosis Mycobacterium tuberculosis] with DAO and GOL as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Beta-ketoacyl-acyl-carrier-protein_synthase_I Beta-ketoacyl-acyl-carrier-protein synthase I], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.3.1.41 2.3.1.41] Full crystallographic information is available from [http:// | + | 1HZP is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Mycobacterium_tuberculosis Mycobacterium tuberculosis] with <scene name='pdbligand=DAO:'>DAO</scene> and <scene name='pdbligand=GOL:'>GOL</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Beta-ketoacyl-acyl-carrier-protein_synthase_I Beta-ketoacyl-acyl-carrier-protein synthase I], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.3.1.41 2.3.1.41] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1HZP OCA]. |
==Reference== | ==Reference== | ||
| Line 16: | Line 16: | ||
[[Category: He, X.]] | [[Category: He, X.]] | ||
[[Category: Kazanina, G.]] | [[Category: Kazanina, G.]] | ||
| - | [[Category: Reynolds, K | + | [[Category: Reynolds, K A.]] |
| - | [[Category: Scarsdale, J | + | [[Category: Scarsdale, J N.]] |
| - | [[Category: TBSGC, TB | + | [[Category: TBSGC, TB Structural Genomics Consortium.]] |
| - | [[Category: Wright, H | + | [[Category: Wright, H T.]] |
[[Category: DAO]] | [[Category: DAO]] | ||
[[Category: GOL]] | [[Category: GOL]] | ||
| Line 31: | Line 31: | ||
[[Category: tbsgc]] | [[Category: tbsgc]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 13:06:28 2008'' |
Revision as of 11:06, 21 February 2008
|
Crystal Structure of the Myobacterium Tuberculosis Beta-Ketoacyl-Acyl Carrier Protein Synthase III
Overview
Mycolic acids (alpha-alkyl-beta-hydroxy long chain fatty acids) cover the surface of mycobacteria, and inhibition of their biosynthesis is an established mechanism of action for several key front-line anti-tuberculosis drugs. In mycobacteria, long chain acyl-CoA products (C(14)-C(26)) generated by a type I fatty-acid synthase can be used directly for the alpha-branch of mycolic acid or can be extended by a type II fatty-acid synthase to make the meromycolic acid (C(50)-C(56)))-derived component. An unusual Mycobacterium tuberculosis beta-ketoacyl-acyl carrier protein (ACP) synthase III (mtFabH) has been identified, purified, and shown to catalyze a Claisen-type condensation between long chain acyl-CoA substrates such as myristoyl-CoA (C(14)) and malonyl-ACP. This enzyme, presumed to play a key role in initiating meromycolic acid biosynthesis, was crystallized, and its structure was determined at 2.1-A resolution. The mtFabH homodimer is closely similar in topology and active-site structure to Escherichia coli FabH (ecFabH), with a CoA/malonyl-ACP-binding channel leading from the enzyme surface to the buried active-site cysteine residue. Unlike ecFabH, mtFabH contains a second hydrophobic channel leading from the active site. In the ecFabH structure, this channel is blocked by a phenylalanine residue, which constrains specificity to acetyl-CoA, whereas in mtFabH, this residue is a threonine, which permits binding of longer acyl chains. This same channel in mtFabH is capped by an alpha-helix formed adjacent to a 4-amino acid sequence insertion, which limits bound acyl chain length to 16 carbons. These observations offer a molecular basis for understanding the unusual substrate specificity of mtFabH and its probable role in regulating the biosynthesis of the two different length acyl chains required for generation of mycolic acids. This mtFabH presents a new target for structure-based design of novel antimycobacterial agents.
About this Structure
1HZP is a Single protein structure of sequence from Mycobacterium tuberculosis with and as ligands. Active as Beta-ketoacyl-acyl-carrier-protein synthase I, with EC number 2.3.1.41 Full crystallographic information is available from OCA.
Reference
Crystal structure of the Mycobacterium tuberculosis beta-ketoacyl-acyl carrier protein synthase III., Scarsdale JN, Kazanina G, He X, Reynolds KA, Wright HT, J Biol Chem. 2001 Jun 8;276(23):20516-22. Epub 2001 Mar 8. PMID:11278743
Page seeded by OCA on Thu Feb 21 13:06:28 2008
Categories: Beta-ketoacyl-acyl-carrier-protein synthase I | Mycobacterium tuberculosis | Single protein | He, X. | Kazanina, G. | Reynolds, K A. | Scarsdale, J N. | TBSGC, TB Structural Genomics Consortium. | Wright, H T. | DAO | GOL | Fatty acid biosynthesis | Myobacterium tuberculosis | Protein structure initiative | Psi | Structural basis for substrate specificity | Structural genomics | Tb structural genomics consortium | Tbsgc
