6c9p | pdb_00006c9p

Mycobacterium tuberculosis adenosine kinase bound to 6-methylmercaptopurine riboside

spinqualitylabelsall models 6c9p, resolution 2.00Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6c9p is a 2 chain structure with sequence from "bacillus_tuberculosis"_(zopf_1883)_klein_1884 "bacillus tuberculosis" (zopf 1883) klein 1884. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: GOL, MTP, NA, SO4 Gene: adoK, cbhK, MRA_2218 ("Bacillus tuberculosis" (Zopf 1883) Klein 1884) Activity: Adenosine kinase, with EC number 2.7.1.20 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [ADOK_MYCTA] Catalyzes the phosphorylation of adenosine to adenosine monophosphate (AMP). Can also catalyze the phosphorylation of the adenosine analog 2-methyladenosine (methyl-Ado) to methyl-AMP, the first step in the metabolism of this compound to an active form that displays antitubercular activity. Is not active on guanosine, inosine, deoxyadenosine, cytidine, uridine, or thymidine. Prefers dGTP and GTP to ATP as phosphate donors in vitro. Publication Abstract from PubMed 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 muM. 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. Structure-Guided Drug Design of 6-Substituted Adenosine Analogues as Potent Inhibitors of Mycobacterium tuberculosis Adenosine Kinase.,Crespo RA, Dang Q, Zhou NE, Guthrie LM, Snavely TC, Dong W, Loesch KA, Suzuki T, You L, Wang W, O'Malley T, Parish T, Olsen DB, Sacchettini JC J Med Chem. 2019 Apr 19. doi: 10.1021/acs.jmedchem.9b00020. PMID:31002508 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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