Structural highlights
4q4r is a 1 chain structure. This structure supersedes the now removed PDB entries and 3gfn. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
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| Ligands: | , , |
| Related: | 4q4m, 4q4o, 4q4p, 4q4q, 4q4s, 1p0d |
| Activity: | tRNA-guanine(34) transglycosylase, with EC number 2.4.2.29 |
| Resources: | FirstGlance, OCA, RCSB, PDBsum |
Function
[TGT_ZYMMO] Exchanges the guanine residue with 7-aminomethyl-7-deazaguanine in tRNAs with GU(N) anticodons (tRNA-Asp, -Asn, -His and -Tyr). After this exchange, a cyclopentendiol moiety is attached to the 7-aminomethyl group of 7-deazaguanine, resulting in the hypermodified nucleoside queuosine (Q) (7-(((4,5-cis-dihydroxy-2-cyclopenten-1-yl)amino)methyl)-7-deazaguanosine).[HAMAP-Rule:MF_00168]
Publication Abstract from PubMed
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.
Beyond Affinity: Enthalpy-Entropy Factorization Unravels Complexity of a Flat Structure-Activity Relationship for Inhibition of a tRNA-Modifying Enzyme.,Neeb M, Betz M, Heine A, Barandun LJ, Hohn C, Diederich F, Klebe G J Med Chem. 2014 Jun 24. PMID:24960372[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Neeb M, Betz M, Heine A, Barandun LJ, 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. 2014 Jun 24. PMID:24960372 doi:http://dx.doi.org/10.1021/jm5006868
