Summary for 9B70
| Entry DOI | 10.2210/pdb9b70/pdb |
| EMDB information | 44293 |
| Descriptor | Phospho-N-acetylmuramoyl-pentapeptide-transferase, MraYAA nanobody, (2~{S},3~{S})-3-[(2~{S},3~{R},4~{S},5~{R})-5-(aminomethyl)-3,4-bis(oxidanyl)oxolan-2-yl]oxy-2-[[3-[[[(2~{S})-6-azanyl-2-(hexadecanoylamino)hexanoyl]amino]methyl]phenyl]methylamino]-3-[(2~{S},3~{S},4~{R},5~{R})-5-[2,4-bis(oxidanylidene)pyrimidin-1-yl]-3,4-bis(oxidanyl)oxolan-2-yl]propanoic acid, ... (4 entities in total) |
| Functional Keywords | inhibitor, antibiotics, transferase |
| Biological source | Aquifex aeolicus VF5 More |
| Total number of polymer chains | 4 |
| Total formula weight | 113892.92 |
| Authors | Hao, A.,Lee, S.-Y. (deposition date: 2024-03-26, release date: 2024-06-26, Last modification date: 2024-10-23) |
| Primary citation | Yamamoto, K.,Sato, T.,Hao, A.,Asao, K.,Kaguchi, R.,Kusaka, S.,Ruddarraju, R.R.,Kazamori, D.,Seo, K.,Takahashi, S.,Horiuchi, M.,Yokota, S.I.,Lee, S.Y.,Ichikawa, S. Development of a natural product optimization strategy for inhibitors against MraY, a promising antibacterial target. Nat Commun, 15:5085-5085, 2024 Cited by PubMed Abstract: MraY (phospho-N-acetylmuramoyl-pentapeptide-transferase) inhibitory natural products are attractive molecules as candidates for a new class of antibacterial agents to combat antimicrobial-resistant bacteria. Structural optimization of these natural products is required to improve their drug-like properties for therapeutic use. However, chemical modifications of these natural products are painstaking tasks due to complex synthetic processes, which is a bottleneck in advancing natural products to the clinic. Here, we develop a strategy for a comprehensive in situ evaluation of the build-up library, which enables us to streamline the preparation of the analogue library and directly assess its biological activities. We apply this approach to a series of MraY inhibitory natural products. Through construction and evaluation of the 686-compound library, we identify promising analogues that exhibit potent and broad-spectrum antibacterial activity against highly drug-resistant strains in vitro as well as in vivo in an acute thigh infection model. Structures of the MraY-analogue complexes reveal distinct interaction patterns, suggesting that these analogues represent MraY inhibitors with unique binding modes. We further demonstrate the generality of our strategy by applying it to tubulin-binding natural products to modulate their tubulin polymerization activities. PubMed: 38877016DOI: 10.1038/s41467-024-49484-7 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (2.88 Å) |
Structure validation
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