6C9P
Mycobacterium tuberculosis adenosine kinase bound to 6-methylmercaptopurine riboside
Summary for 6C9P
| Entry DOI | 10.2210/pdb6c9p/pdb |
| Descriptor | Adenosine kinase, SULFATE ION, SODIUM ION, ... (6 entities in total) |
| Functional Keywords | nucleoside analog, complex, inhibitor, structural genomics, psi-2, protein structure initiative, tb structural genomics consortium, tbsgc, transferase-transferase inhibitor complex, transferase/transferase inhibitor |
| Biological source | Mycobacterium tuberculosis |
| Total number of polymer chains | 2 |
| Total formula weight | 70531.38 |
| Authors | Crespo, R.A.,TB Structural Genomics Consortium (TBSGC) (deposition date: 2018-01-28, release date: 2019-05-01, Last modification date: 2023-10-04) |
| Primary citation | 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 Cited by 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: 31002508DOI: 10.1021/acs.jmedchem.9b00020 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2 Å) |
Structure validation
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