7A20

Azobenzene-Based Inhibitors for Tryptophan Synthase

Summary for 7A20

• Entry DOI: 10.2210/pdb7a20/pdb
• Descriptor: Tryptophan synthase alpha chain,Tryptophan synthase beta chain, SODIUM ION, TRIS-HYDROXYMETHYL-METHYL-AMMONIUM, ... (4 entities in total)
• Functional Keywords: antibiotics, enzymes, inhibitors, photopharmacology, photoswitches, antibiotic
• Biological source: Salmonella typhimurium; More
• Total number of polymer chains: 4
• Total formula weight: 306114.58

Authors

Rajendran, C.,Sterner, R. (deposition date: 2020-08-14, release date: 2020-11-04, Last modification date: 2024-05-15)

Primary citation

Simeth, N.A.,Kinateder, T.,Rajendran, C.,Nazet, J.,Merkl, R.,Sterner, R.,Konig, B.,Kneuttinger, A.C.
Towards Photochromic Azobenzene-Based Inhibitors for Tryptophan Synthase.
Chemistry, 27:2439-2451, 2021

PubMed Abstract: Light regulation of drug molecules has gained growing interest in biochemical and pharmacological research in recent years. In addition, a serious need for novel molecular targets of antibiotics has emerged presently. Herein, the development of a photocontrollable, azobenzene-based antibiotic precursor towards tryptophan synthase (TS), an essential metabolic multienzyme complex in bacteria, is presented. The compound exhibited moderately strong inhibition of TS in its E configuration and five times lower inhibition strength in its Z configuration. A combination of biochemical, crystallographic, and computational analyses was used to characterize the inhibition mode of this compound. Remarkably, binding of the inhibitor to a hitherto-unconsidered cavity results in an unproductive conformation of TS leading to noncompetitive inhibition of tryptophan production. In conclusion, we created a promising lead compound for combatting bacterial diseases, which targets an essential metabolic enzyme, and whose inhibition strength can be controlled with light.

PubMed: 33078454
DOI: 10.1002/chem.202004061

Experimental method

X-RAY DIFFRACTION (2.5 Å)