7Q2C

mycolic acid methyltransferase Hma (MmaA4) from Mycobac-terium tuberculosis in complex with ZT260

7Q2C の概要

• エントリーDOI: 10.2210/pdb7q2c/pdb
• 関連するPDBエントリー: 7Q2B 7Q2D 7Q2E 7Q2F 7Q2G 7Q2H
• 分子名称: Hydroxymycolate synthase MmaA4, DIMETHYL SULFOXIDE, 6-methyl-2H-chromen-2-one, ... (4 entities in total)
• 機能のキーワード: mycolic acid methyltransferase mycobacterium tuberculosis fragment based ligand discovery, transferase
• 由来する生物種: Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 37076.04

構造登録者

Maveyraud, L.,Galy, R.,Mourey, L. (登録日: 2021-10-25, 公開日: 2022-02-02, 最終更新日: 2024-01-31)

主引用文献

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

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: 34959681
DOI: 10.3390/ph14121282

実験手法

X-RAY DIFFRACTION (1.9 Å)