6C9S

Mycobacterium tuberculosis adenosine kinase bound to (2R,3R,4S,5R)-2-(6-([1,1'-biphenyl]-4-ylethynyl)-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol

6C9S の概要

• エントリーDOI: 10.2210/pdb6c9s/pdb
• 分子名称: Adenosine kinase, 6-[([1,1'-biphenyl]-4-yl)ethynyl]-9-beta-D-ribofuranosyl-9H-purine, SULFATE ION, ... (5 entities in total)
• 機能のキーワード: nucleoside analog, complex, inhibitor, structural genomics, psi-2, protein structure initiative, tb structural genomics consortium, tbsgc, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Mycobacterium tuberculosis
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 70102.89

構造登録者

Crespo, R.A.,TB Structural Genomics Consortium (TBSGC) (登録日: 2018-01-28, 公開日: 2019-05-01, 最終更新日: 2023-10-04)

主引用文献

Crespo, R.A.,Dang, Q.,Zhou, N.E.,Guthrie, L.M.,Snavely, T.C.,Dong, W.,Loesch, K.A.,Suzuki, T.,You, L.,Wang, W.,O'Malley, T.,Parish, T.,Olsen, D.B.,Sacchettini, J.C.
Structure-Guided Drug Design of 6-Substituted Adenosine Analogues as Potent Inhibitors of Mycobacterium tuberculosis Adenosine Kinase.
J.Med.Chem., 62:4483-4499, 2019

PubMed Abstract: Mycobacterium tuberculosis adenosine kinase (MtbAdoK) is an essential enzyme of Mtb and forms part of the purine salvage pathway within mycobacteria. Evidence suggests that the purine salvage pathway might play a crucial role in Mtb survival and persistence during its latent phase of infection. In these studies, we adopted a structural approach to the discovery, structure-guided design, and synthesis of a series of adenosine analogues that displayed inhibition constants ranging from 5 to 120 nM against the enzyme. Two of these compounds exhibited low micromolar activity against Mtb with half maximal effective inhibitory concentrations of 1.7 and 4.0 μM. Our selectivity and preliminary pharmacokinetic studies showed that the compounds possess a higher degree of specificity against MtbAdoK when compared with the human counterpart and are well tolerated in rodents, respectively. Finally, crystallographic studies showed the molecular basis of inhibition, potency, and selectivity and revealed the presence of a potentially therapeutically relevant cavity unique to the MtbAdoK homodimer.

PubMed: 31002508
DOI: 10.1021/acs.jmedchem.9b00020

実験手法

X-RAY DIFFRACTION (2.23 Å)