6NPF
Structure of E.coli enolase in complex with an analog of the natural product SF-2312 metabolite.
Summary for 6NPF
| Entry DOI | 10.2210/pdb6npf/pdb |
| Related | 6D3Q |
| Descriptor | Enolase, L(+)-TARTARIC ACID, SULFATE ION, ... (7 entities in total) |
| Functional Keywords | natural inhibitor, complex, enolase, sf2312, lyase |
| Biological source | Escherichia coli |
| Total number of polymer chains | 6 |
| Total formula weight | 286848.39 |
| Authors | Erlandsen, H.,Krucinska, J.,Lombardo, M.,Wright, D. (deposition date: 2019-01-17, release date: 2019-11-27, Last modification date: 2023-10-11) |
| Primary citation | Krucinska, J.,Lombardo, M.N.,Erlandsen, H.,Hazeen, A.,Duay, S.S.,Pattis, J.G.,Robinson, V.L.,May, E.R.,Wright, D.L. Functional and structural basis of E. coli enolase inhibition by SF2312: a mimic of the carbanion intermediate. Sci Rep, 9:17106-17106, 2019 Cited by PubMed Abstract: Many years ago, the natural secondary metabolite SF2312, produced by the actinomycete Micromonospora, was reported to display broad spectrum antibacterial properties against both Gram-positive and Gram-negative bacteria. Recent studies have revealed that SF2312, a natural phosphonic acid, functions as a potent inhibitor of human enolase. The mechanism of SF2312 inhibition of bacterial enolase and its role in bacterial growth and reproduction, however, have remained elusive. In this work, we detail a structural analysis of E. coli enolase bound to both SF2312 and its oxidized imide-form. Our studies support a model in which SF2312 acts as an analog of a high energy intermediate formed during the catalytic process. Biochemical, biophysical, computational and kinetic characterization of these compounds confirm that altering features characteristic of a putative carbanion (enolate) intermediate significantly reduces the potency of enzyme inhibition. When SF2312 is combined with fosfomycin in the presence of glucose-6 phosphate, significant synergy is observed. This suggests the two agents could be used as a potent combination, targeting distinct cellular mechanism for the treatment of bacterial infections. Together, our studies rationalize the structure-activity relationships for these phosphonates and validate enolase as a promising target for antibiotic discovery. PubMed: 31745118DOI: 10.1038/s41598-019-53301-3 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.57 Å) |
Structure validation
Download full validation report
