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 1.9&Aring;" /> '''CRYSTAL STRUCTURE OF ...)
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'''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==
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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.
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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==
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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://ispc.weizmann.ac.il/oca-bin/ocashort?id=1I8J OCA].
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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]]
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[[Category: Jaffe, E.K.]]
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[[Category: Jaffe, E K.]]
[[Category: Kervinen, J.]]
[[Category: Kervinen, J.]]
[[Category: Neier, R.]]
[[Category: Neier, R.]]
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[[Category: zinc]]
[[Category: zinc]]
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''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

Image:1i8j.jpg

1i8j, resolution 1.9Å

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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

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