7Q2H
mycolic acid methyltransferase Hma (MmaA4) from Mycobac-terium tuberculosis in complex with ZT275
Summary for 7Q2H
| Entry DOI | 10.2210/pdb7q2h/pdb |
| Related | 7Q2B 7Q2C 7Q2D 7Q2E 7Q2F 7Q2G |
| Descriptor | Hydroxymycolate synthase MmaA4, O-TOLUENESULFONAMIDE, DIMETHYL SULFOXIDE, ... (5 entities in total) |
| Functional Keywords | mycolic acid methyltransferase mycobacterium tuberculosis fragment based ligand discovery, transferase |
| Biological source | Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv) |
| Total number of polymer chains | 1 |
| Total formula weight | 36988.99 |
| Authors | Maveyraud, L.,Galy, R.,Mourey, L. (deposition date: 2021-10-25, release date: 2022-02-02, Last modification date: 2024-01-31) |
| Primary citation | Galy, R.,Ballereau, S.,Genisson, Y.,Mourey, L.,Plaquevent, J.C.,Maveyraud, L. Fragment-Based Ligand Discovery Applied to the Mycolic Acid Methyltransferase Hma (MmaA4) from Mycobacterium tuberculosis : A Crystallographic and Molecular Modelling Study. Pharmaceuticals, 14:-, 2021 Cited by PubMed Abstract: The mycolic acid biosynthetic pathway represents a promising source of pharmacological targets in the fight against tuberculosis. In , mycolic acids are subject to specific chemical modifications introduced by a set of eight S-adenosylmethionine dependent methyltransferases. Among these, Hma (MmaA4) is responsible for the introduction of oxygenated modifications. Crystallographic screening of a library of fragments allowed the identification of seven ligands of Hma. Two mutually exclusive binding modes were identified, depending on the conformation of residues 147-154. These residues are disordered in -Hma but fold upon binding of the S-adenosylmethionine (SAM) cofactor as well as of analogues, resulting in the formation of the short η1-helix. One of the observed conformations would be incompatible with the presence of the cofactor, suggesting that allosteric inhibitors could be designed against Hma. Chimeric compounds were designed by fusing some of the bound fragments, and the relative binding affinities of initial fragments and evolved compounds were investigated using molecular dynamics simulation and generalised Born and Poisson-Boltzmann calculations coupled to the surface area continuum solvation method. Molecular dynamics simulations were also performed on -Hma to assess the structural plasticity of the unliganded protein. Our results indicate a significant improvement in the binding properties of the designed compounds, suggesting that they could be further optimised to inhibit Hma activity. PubMed: 34959681DOI: 10.3390/ph14121282 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.75 Å) |
Structure validation
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