6S88
Fumarate hydratase of Mycobacterium tuberculosis in complex with formate and allosteric modulator N-(2-Methoxy-5-((1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)sulfonyl)phenyl)-2-(4-oxo-3,4-dihydrophthalazin-1-yl)acetamide
Summary for 6S88
| Entry DOI | 10.2210/pdb6s88/pdb |
| Descriptor | Fumarate hydratase class II, ~{N}-[2-methoxy-5-(1,2,4,5-tetrahydro-3-benzazepin-3-ylsulfonyl)phenyl]-2-(4-oxidanylidene-3~{H}-phthalazin-1-yl)ethanamide, FORMIC ACID, ... (5 entities in total) |
| Functional Keywords | fumarate hydratase, fumarase, lyase |
| Biological source | Mycobacterium tuberculosis |
| Total number of polymer chains | 4 |
| Total formula weight | 201874.72 |
| Authors | Whitehouse, A.J.,Libardo, M.D.,Kasbekar, M.,Brear, P.,Fischer, G.,Thomas, C.J.,Barry, C.E.,Boshoff, H.I.,Coyne, A.G.,Abell, C. (deposition date: 2019-07-08, release date: 2019-09-25, Last modification date: 2024-01-24) |
| Primary citation | Whitehouse, A.J.,Libardo, M.D.J.,Kasbekar, M.,Brear, P.D.,Fischer, G.,Thomas, C.J.,Barry 3rd, C.E.,Boshoff, H.I.M.,Coyne, A.G.,Abell, C. Targeting of Fumarate Hydratase fromMycobacterium tuberculosisUsing Allosteric Inhibitors with a Dimeric-Binding Mode. J.Med.Chem., 62:10586-10604, 2019 Cited by PubMed Abstract: With the growing worldwide prevalence of antibiotic-resistant strains of tuberculosis (TB), new targets are urgently required for the development of treatments with novel modes of action. Fumarate hydratase (fumarase), a vulnerable component of the citric acid cycle in (), is a metabolic target that could satisfy this unmet demand. A key challenge in the targeting of fumarase is its similarity to the human homolog, which shares an identical active site. A potential solution to this selectivity problem was previously found in a high-throughput screening hit that binds in a nonconserved allosteric site. In this work, a structure-activity relationship study was carried out with the determination of further structural biology on the lead series, affording derivatives with sub-micromolar inhibition. Further, the screening of this series against in vitro identified compounds with potent minimum inhibitory concentrations. PubMed: 31517489DOI: 10.1021/acs.jmedchem.9b01203 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.59 Å) |
Structure validation
Download full validation report
