1i8j

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spinqualitylabelsall models 1i8j, resolution 1.9Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

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 ZN, MG and DSB 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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