5WLY
E. coli LpxH- 8 mutations
Summary for 5WLY
| Entry DOI | 10.2210/pdb5wly/pdb |
| Descriptor | UDP-2,3-diacylglucosamine hydrolase, MANGANESE (II) ION, CHLORIDE ION, ... (6 entities in total) |
| Functional Keywords | lipid a synthesis, open conformation, udp-diacyl-glucosamine pyrophosphohydrolase, apha/beta-hydrolase, hydrolase |
| Biological source | Escherichia coli |
| Total number of polymer chains | 1 |
| Total formula weight | 27985.40 |
| Authors | Bohl, T.E.,Aihara, H.,Shi, K.,Lee, J.K. (deposition date: 2017-07-28, release date: 2018-04-11, Last modification date: 2023-10-04) |
| Primary citation | Bohl, T.E.,Ieong, P.,Lee, J.K.,Lee, T.,Kankanala, J.,Shi, K.,Demir, O.,Kurahashi, K.,Amaro, R.E.,Wang, Z.,Aihara, H. The substrate-binding cap of the UDP-diacylglucosamine pyrophosphatase LpxH is highly flexible, enabling facile substrate binding and product release. J. Biol. Chem., 293:7969-7981, 2018 Cited by PubMed Abstract: Gram-negative bacteria are surrounded by a secondary membrane of which the outer leaflet is composed of the glycolipid lipopolysaccharide (LPS), which guards against hydrophobic toxins, including many antibiotics. Therefore, LPS synthesis in bacteria is an attractive target for antibiotic development. LpxH is a pyrophosphatase involved in LPS synthesis, and previous structures revealed that LpxH has a helical cap that binds its lipid substrates. Here, crystallography and hydrogen-deuterium exchange MS provided evidence for a highly flexible substrate-binding cap in LpxH. Furthermore, molecular dynamics simulations disclosed how the helices of the cap may open to allow substrate entry. The predicted opening mechanism was supported by activity assays of LpxH variants. Finally, we confirmed biochemically that LpxH is inhibited by a previously identified antibacterial compound, determined the potency of this inhibitor, and modeled its binding mode in the LpxH active site. In summary, our work provides evidence that the substrate-binding cap of LpxH is highly dynamic, thus allowing for facile substrate binding and product release between the capping helices. Our results also pave the way for the rational design of more potent LpxH inhibitors. PubMed: 29626094DOI: 10.1074/jbc.RA118.002503 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2 Å) |
Structure validation
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