7MLO
Crystal structure of ricin A chain in complex with 5-mesitylthiophene-2-carboxylic acid
Summary for 7MLO
| Entry DOI | 10.2210/pdb7mlo/pdb |
| Descriptor | Ricin, 5-(2,4,6-trimethylphenyl)thiophene-2-carboxylic acid, 1,2-ETHANEDIOL, ... (5 entities in total) |
| Functional Keywords | ricin chain-a, rta, hydrolase, toxin, inhibitor, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor |
| Biological source | Ricinus communis (Castor bean) |
| Total number of polymer chains | 2 |
| Total formula weight | 60910.82 |
| Authors | Harijan, R.K.,Li, X.P.,Cao, B.,Augeri, D.,Bonanno, J.B.,Almo, S.C.,Tumer, N.E.,Schramm, V.L. (deposition date: 2021-04-28, release date: 2022-02-09, Last modification date: 2023-10-18) |
| Primary citation | Li, X.P.,Harijan, R.K.,Cao, B.,Kahn, J.N.,Pierce, M.,Tsymbal, A.M.,Roberge, J.Y.,Augeri, D.,Tumer, N.E. Synthesis and Structural Characterization of Ricin Inhibitors Targeting Ribosome Binding Using Fragment-Based Methods and Structure-Based Design. J.Med.Chem., 64:15334-15348, 2021 Cited by PubMed Abstract: Ricin toxin A subunit (RTA) is the catalytic subunit of ricin, which depurinates an adenine from the sarcin/ricin loop in eukaryotic ribosomes. There are no approved inhibitors against ricin. We used a new strategy to disrupt RTA-ribosome interactions by fragment screening using surface plasmon resonance. Here, using a structure-guided approach, we improved the affinity and inhibitory activity of small-molecular-weight lead compounds and obtained improved compounds with over an order of magnitude higher efficiency. Four advanced compounds were characterized by X-ray crystallography. They bind at the RTA-ribosome binding site as the original compound but in a distinctive manner. These inhibitors bind remotely from the catalytic site and cause local conformational changes with no alteration of the catalytic site geometry. Yet they inhibit depurination by ricin holotoxin and inhibit the cytotoxicity of ricin in mammalian cells. They are the first agents that protect against ricin holotoxin by acting directly on RTA. PubMed: 34648707DOI: 10.1021/acs.jmedchem.1c01370 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.65 Å) |
Structure validation
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