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1i8j
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(New page: 200px<br /><applet load="1i8j" size="450" color="white" frame="true" align="right" spinBox="true" caption="1i8j, resolution 1.9Å" /> '''CRYSTAL STRUCTURE OF ...) |
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| - | [[Image:1i8j.jpg|left|200px]]<br /><applet load="1i8j" size=" | + | [[Image:1i8j.jpg|left|200px]]<br /><applet load="1i8j" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="1i8j, resolution 1.9Å" /> | caption="1i8j, resolution 1.9Å" /> | ||
'''CRYSTAL STRUCTURE OF PORPHOBILINOGEN SYNTHASE COMPLEXED WITH THE INHIBITOR 4,7-DIOXOSEBACIC ACID'''<br /> | '''CRYSTAL STRUCTURE OF PORPHOBILINOGEN SYNTHASE COMPLEXED WITH THE INHIBITOR 4,7-DIOXOSEBACIC ACID'''<br /> | ||
==Overview== | ==Overview== | ||
| - | 4,7-Dioxosebacic acid (4,7-DOSA) is an active site-directed irreversible | + | 4,7-Dioxosebacic acid (4,7-DOSA) is an active site-directed irreversible inhibitor of porphobilinogen synthase (PBGS). PBGS catalyzes the first common step in the biosynthesis of the tetrapyrrole cofactors such as heme, vitamin B(12), and chlorophyll. 4,7-DOSA was designed as an analogue of a proposed reaction intermediate in the physiological PBGS-catalyzed condensation of two molecules of 5-aminolevulinic acid. As shown here, 4,7-DOSA exhibits time-dependent and dramatic species-specific inhibition of PBGS enzymes. IC(50) values vary from 1 microM to 2.4 mM for human, Escherichia coli, Bradyrhizobium japonicum, Pseudomonas aeruginosa, and pea enzymes. Those PBGS utilizing a catalytic Zn(2+) are more sensitive to 4,7-DOSA than those that do not. Weak inhibition of a human mutant PBGS establishes that the inactivation by 4,7-DOSA requires formation of a Schiff base to a lysine that normally forms a Schiff base intermediate to one substrate molecule. A 1.9 A resolution crystal structure of E. coli PBGS complexed with 4,7-DOSA (PDB code ) shows one dimer per asymmetric unit and reveals that the inhibitor forms two Schiff base linkages with each monomer, one to the normal Schiff base-forming Lys-246 and the other to a universally conserved "perturbing" Lys-194 (E. coli numbering). This is the first structure to show inhibitor binding at the second of two substrate-binding sites. |
==About this Structure== | ==About this Structure== | ||
| - | 1I8J 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 ZN, MG and DSB as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Porphobilinogen_synthase Porphobilinogen synthase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=4.2.1.24 4.2.1.24] Full crystallographic information is available from [http:// | + | 1I8J 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=ZN:'>ZN</scene>, <scene name='pdbligand=MG:'>MG</scene> and <scene name='pdbligand=DSB:'>DSB</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Porphobilinogen_synthase Porphobilinogen synthase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=4.2.1.24 4.2.1.24] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1I8J OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Porphobilinogen synthase]] | [[Category: Porphobilinogen synthase]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Jaffe, E | + | [[Category: Jaffe, E K.]] |
[[Category: Kervinen, J.]] | [[Category: Kervinen, J.]] | ||
[[Category: Neier, R.]] | [[Category: Neier, R.]] | ||
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[[Category: zinc]] | [[Category: zinc]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 13:09:08 2008'' |
Revision as of 11:09, 21 February 2008
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CRYSTAL STRUCTURE OF PORPHOBILINOGEN SYNTHASE COMPLEXED WITH THE INHIBITOR 4,7-DIOXOSEBACIC ACID
Overview
4,7-Dioxosebacic acid (4,7-DOSA) is an active site-directed irreversible inhibitor of porphobilinogen synthase (PBGS). PBGS catalyzes the first common step in the biosynthesis of the tetrapyrrole cofactors such as heme, vitamin B(12), and chlorophyll. 4,7-DOSA was designed as an analogue of a proposed reaction intermediate in the physiological PBGS-catalyzed condensation of two molecules of 5-aminolevulinic acid. As shown here, 4,7-DOSA exhibits time-dependent and dramatic species-specific inhibition of PBGS enzymes. IC(50) values vary from 1 microM to 2.4 mM for human, Escherichia coli, Bradyrhizobium japonicum, Pseudomonas aeruginosa, and pea enzymes. Those PBGS utilizing a catalytic Zn(2+) are more sensitive to 4,7-DOSA than those that do not. Weak inhibition of a human mutant PBGS establishes that the inactivation by 4,7-DOSA requires formation of a Schiff base to a lysine that normally forms a Schiff base intermediate to one substrate molecule. A 1.9 A resolution crystal structure of E. coli PBGS complexed with 4,7-DOSA (PDB code ) shows one dimer per asymmetric unit and reveals that the inhibitor forms two Schiff base linkages with each monomer, one to the normal Schiff base-forming Lys-246 and the other to a universally conserved "perturbing" Lys-194 (E. coli numbering). This is the first structure to show inhibitor binding at the second of two substrate-binding sites.
About this Structure
1I8J is a Single protein structure of sequence from Escherichia coli with , and as ligands. Active as Porphobilinogen synthase, with EC number 4.2.1.24 Full crystallographic information is available from OCA.
Reference
Mechanistic basis for suicide inactivation of porphobilinogen synthase by 4,7-dioxosebacic acid, an inhibitor that shows dramatic species selectivity., Kervinen J, Jaffe EK, Stauffer F, Neier R, Wlodawer A, Zdanov A, Biochemistry. 2001 Jul 27;40(28):8227-36. PMID:11444968
Page seeded by OCA on Thu Feb 21 13:09:08 2008
Categories: Escherichia coli | Porphobilinogen synthase | Single protein | Jaffe, E K. | Kervinen, J. | Neier, R. | Stauffer, F. | Wlodawer, A. | Zdanov, A. | DSB | MG | ZN | 4 | 7-dioxosebacic acid | Heme biosynthesis | Lyase | Magnesium | Zinc
