5UMY

Crystal structure of TnmS3 in complex with tiancimycin

Summary for 5UMY

• Entry DOI: 10.2210/pdb5umy/pdb
• Descriptor: Glyoxalase/bleomycin resisance protein/dioxygenase, (1aS,11S,11aR,14Z,18R)-3,8,18-trihydroxy-11a-[(1R)-1-hydroxyethyl]-7-methoxy-11,11a-dihydro-4H-11,1a-hept[3]ene[1,5]diynonaphtho[2,3-h]oxireno[c]quinoline-4,9(10H)-dione (3 entities in total)
• Functional Keywords: glyoxalase/bleomycin resistance protein/dioxygenase superfamily, structural genomics, psi-biology, midwest center for structural genomics, mcsg, enzyme discovery for natural product biosynthesis, natpro, lyase, tiancimycin-binding protein
• Biological source: Streptomyces sp. CB03234
• Total number of polymer chains: 2
• Total formula weight: 31276.73

Authors

Chang, C.Y.,Chang, C.,Nocek, B.,Rudolf, J.D.,Joachimiak, A.,Phillips Jr., G.N.,SHen, B.,Enzyme Discovery for Natural Product Biosynthesis (NatPro),Midwest Center for Structural Genomics (MCSG) (deposition date: 2017-01-29, release date: 2018-07-04, Last modification date: 2023-10-04)

Primary citation

Chang, C.Y.,Yan, X.,Crnovcic, I.,Annaval, T.,Chang, C.,Nocek, B.,Rudolf, J.D.,Yang, D.,Babnigg, G.,Joachimiak, A.,Phillips Jr., G.N.,Shen, B.
Resistance to Enediyne Antitumor Antibiotics by Sequestration.
Cell Chem Biol, 25:1075-1085.e4, 2018

PubMed Abstract: The enediynes, microbial natural products with extraordinary cytotoxicities, have been translated into clinical drugs. Two self-resistance mechanisms are known in the enediyne producers-apoproteins for the nine-membered enediynes and self-sacrifice proteins for the ten-membered enediyne calicheamicin. Here we show that: (1) tnmS1, tnmS2, and tnmS3 encode tiancimycin (TNM) resistance in its producer Streptomyces sp. CB03234, (2) tnmS1, tnmS2, and tnmS3 homologs are found in all anthraquinone-fused enediyne producers, (3) TnmS1, TnmS2, and TnmS3 share a similar β barrel-like structure, bind TNMs with nanomolar K values, and confer resistance by sequestration, and (4) TnmS1, TnmS2, and TnmS3 homologs are widespread in nature, including in the human microbiome. These findings unveil an unprecedented resistance mechanism for the enediynes. Mechanisms of self-resistance in producers serve as models to predict and combat future drug resistance in clinical settings. Enediyne-based chemotherapies should now consider the fact that the human microbiome harbors genes encoding enediyne resistance.

PubMed: 29937405
DOI: 10.1016/j.chembiol.2018.05.012

Experimental method

X-RAY DIFFRACTION (1.78 Å)