2WOQ
Porphobilinogen Synthase (HemB) in Complex with 5-acetamido-4- oxohexanoic acid (Alaremycin 2)
Summary for 2WOQ
| Entry DOI | 10.2210/pdb2woq/pdb |
| Related | 1B4K 1GZG 1W54 1W56 1W5M 1W5N 1W5O 1W5P 1W5Q 2C13 2C14 2C15 2C16 2C18 2C19 |
| Descriptor | DELTA-AMINOLEVULINIC ACID DEHYDRATASE, ALAREMYCIN 2, MAGNESIUM ION, ... (6 entities in total) |
| Functional Keywords | lyase-antibiotic complex, lyase antibiotic complex, metal-binding, heme biosynthesis, porphyrin biosynthesis, porpobilinogen synthase, hemb, lyase, inhibitor, lyase/antibiotic |
| Biological source | PSEUDOMONAS AERUGINOSA |
| Total number of polymer chains | 1 |
| Total formula weight | 39432.90 |
| Authors | Heinemann, I.U.,Schulz, C.,Schubert, W.-D.,Heinz, D.W.,Wang, Y.-G.,Kobayashi, Y.,Awa, Y.,Wachi, M.,Jahn, D.,Jahn, M. (deposition date: 2009-07-27, release date: 2009-10-27, Last modification date: 2024-10-16) |
| Primary citation | Heinemann, I.U.,Schulz, C.,Schubert, W.D.,Heinz, D.W.,Wang, Y.G.,Kobayashi, Y.,Awa, Y.,Wachi, M.,Jahn, D.,Jahn, M. Structure of the heme biosynthetic Pseudomonas aeruginosa porphobilinogen synthase in complex with the antibiotic alaremycin. Antimicrob. Agents Chemother., 54:267-272, 2010 Cited by PubMed Abstract: The recently discovered antibacterial compound alaremycin, produced by Streptomyces sp. A012304, structurally closely resembles 5-aminolevulinic acid, the substrate of porphobilinogen synthase. During the initial steps of heme biosynthesis, two molecules of 5-aminolevulinic acid are asymmetrically condensed to porphobilinogen. Alaremycin was found to efficiently inhibit the growth of both Gram-negative and Gram-positive bacteria. Using the newly created heme-permeable strain Escherichia coli CSA1, we are able to uncouple heme biosynthesis from bacterial growth and demonstrate that alaremycin targets the heme biosynthetic pathway. Further studies focused on the activity of alaremycin against the opportunistic pathogenic bacterium Pseudomonas aeruginosa. The MIC of alaremycin was determined to be 12 mM. Alaremycin was identified as a direct inhibitor of recombinant purified P. aeruginosa porphobilinogen synthase and had a K(i) of 1.33 mM. To understand the molecular basis of alaremycin's antibiotic activity at the atomic level, the P. aeruginosa porphobilinogen synthase was cocrystallized with the alaremycin. At 1.75-A resolution, the crystal structure reveals that the antibiotic efficiently blocks the active site of porphobilinogen synthase. The antibiotic binds as a reduced derivative of 5-acetamido-4-oxo-5-hexenoic acid. The corresponding methyl group is, however, not coordinated by any amino acid residues of the active site, excluding its functional relevance for alaremycin inhibition. Alaremycin is covalently bound by the catalytically important active-site lysine residue 260 and is tightly coordinated by several active-site amino acids. Our data provide a solid structural basis to further improve the activity of alaremycin for rational drug design. Potential approaches are discussed. PubMed: 19822707DOI: 10.1128/AAC.00553-09 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.75 Å) |
Structure validation
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