5NJI

Structure of the dehydratase domain of PpsC from Mycobacterium tuberculosis in complex with C12:1-CoA

Replaces:  5CF7

Summary for 5NJI

• Entry DOI: 10.2210/pdb5nji/pdb
• Related: 4ooc 5i0k 5l84
• Descriptor: Phthiocerol/phenolphthiocerol synthesis polyketide synthase type I PpsC, ~{S}-[2-[3-[[(2~{R})-4-[[[(2~{R},3~{S},4~{R},5~{R})-5-(6-aminopurin-9-yl)-4-oxidanyl-3-phosphonooxy-oxolan-2-yl]methoxy-oxidanyl-phosphoryl]oxy-oxidanyl-phosphoryl]oxy-3,3-dimethyl-2-oxidanyl-butanoyl]amino]propanoylamino]ethyl] (~{E})-dodec-2-enethioate (3 entities in total)
• Functional Keywords: dehydratase, polyketide, complex, tuberculosis, transferase
• Biological source: Mycobacterium tuberculosis
• Total number of polymer chains: 1
• Total formula weight: 35259.16

Authors

Gavalda, S.,Faille, A.,Mourey, L.,Pedelacq, J.D. (deposition date: 2017-03-28, release date: 2017-05-31, Last modification date: 2024-01-17)

Primary citation

Faille, A.,Gavalda, S.,Slama, N.,Lherbet, C.,Maveyraud, L.,Guillet, V.,Laval, F.,Quemard, A.,Mourey, L.,Pedelacq, J.D.
Insights into Substrate Modification by Dehydratases from Type I Polyketide Synthases.
J. Mol. Biol., 429:1554-1569, 2017

PubMed Abstract: Dehydration reactions play a crucial role in the de novo biosynthesis of fatty acids and a wide range of pharmacologically active polyketide natural products with strong emphasis on human medicine. The type I polyketide synthase PpsC from Mycobacterium tuberculosis catalyzes key biosynthetic steps of lipid virulence factors phthiocerol dimycocerosates and phenolic glycolipids. Given the insolubility of the natural C-C fatty acyl substrate of the PpsC dehydratase (DH) domain, we investigated its structure-function relationships in the presence of shorter surrogate substrates. Since most enzymes belonging to the (R)-specific enoyl hydratase/hydroxyacyl dehydratase family conduct the reverse hydration reaction in vitro, we have determined the X-ray structures of the PpsC DH domain, both unliganded (apo) and in complex with trans-but-2-enoyl-CoA or trans-dodec-2-enoyl-CoA derivatives. This study provides for the first time a snapshot of dehydratase-ligand interactions following a hydration reaction. Our structural analysis allowed us to identify residues essential for substrate binding and activity. The structural comparison of the two complexes also sheds light on the need for long acyl chains for this dehydratase to carry out its function, consistent with both its in vitro catalytic behavior and the physiological role of the PpsC enzyme.

PubMed: 28377293
DOI: 10.1016/j.jmb.2017.03.026

Experimental method

X-RAY DIFFRACTION (1.6 Å)