4Q4Q

tRNA-Guanine Transglycosylase (TGT) in Complex with 2-[(Thiophen-2-ylmethyl)amino]-1H,7H,8H-imidazo[4,5-g]quinazolin-8-one

Replaces:  3GEV

Summary for 4Q4Q

• Entry DOI: 10.2210/pdb4q4q/pdb
• Related: 1P0D 4Q4M 4Q4O 4Q4P 4Q4R 4Q4S
• Descriptor: Queuine tRNA-ribosyltransferase, ZINC ION, GLYCEROL, ... (5 entities in total)
• Functional Keywords: transferase, guanine exchange enzyme, preq1, trna, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Zymomonas mobilis subsp. mobilis
• Total number of polymer chains: 1
• Total formula weight: 43656.82

Authors

Neeb, M.,Heine, A.,Klebe, G. (deposition date: 2014-04-15, release date: 2014-07-09, Last modification date: 2023-09-20)

Primary citation

Neeb, M.,Betz, M.,Heine, A.,Barandun, L.J.,Hohn, C.,Diederich, F.,Klebe, G.
Beyond Affinity: Enthalpy-Entropy Factorization Unravels Complexity of a Flat Structure-Activity Relationship for Inhibition of a tRNA-Modifying Enzyme.
J.Med.Chem., 57:5566-5578, 2014

PubMed Abstract: Lead optimization focuses on binding-affinity improvement. If a flat structure-activity relationship is detected, usually optimization strategies are abolished as unattractive. Nonetheless, as affinity is composed of an enthalpic and entropic contribution, factorization of both can unravel the complexity of a flat, on first sight tedious SAR. In such cases, the binding free energy of different ligands can be rather similar, but it can factorize into enthalpy and entropy distinctly. We investigated the thermodynamic signature of two classes of lin-benzopurines binding to tRNA-guanine transglycosylase. While the differences are hardly visible in the free energy, they involve striking enthalpic and entropic changes. Analyzing thermodynamics along with structural features revealed that one ligand set binds to the protein without inducing significant changes compared to the apo structure; however, the second series provokes complex adaptation, leading to a conformation similar to the substrate-bound state. In the latter state, a cross-talk between two pockets is suggested.

PubMed: 24960372
DOI: 10.1021/jm5006868

Experimental method

X-RAY DIFFRACTION (1.41 Å)