4RLW

Crystal Structure of (3R)-hydroxyacyl-ACP dehydratase HadAB hetero-dimer from Mycobacterium tuberculosis complexed with Butein

Summary for 4RLW

• Entry DOI: 10.2210/pdb4rlw/pdb
• Related: 4RLJ 4RLT 4RLU
• Descriptor: (3R)-hydroxyacyl-ACP dehydratase subunit HadA, (3R)-hydroxyacyl-ACP dehydratase subunit HadB, (2E)-1-(2,4-dihydroxyphenyl)-3-(3,4-dihydroxyphenyl)prop-2-en-1-one, ... (5 entities in total)
• Functional Keywords: double hotdog fold, (3r)-hydroxyacyl-acp binding, lyase, lyase-lyase inhibitor complex, lyase/lyase inhibitor
• Biological source: Mycobacterium tuberculosis H37Rv; More
• Total number of polymer chains: 2
• Total formula weight: 33283.28

Authors

Li, J.,Dong, Y.,Rao, Z.H. (deposition date: 2014-10-18, release date: 2015-10-21, Last modification date: 2023-09-20)

Primary citation

Dong, Y.,Qiu, X.,Shaw, N.,Xu, Y.,Sun, Y.,Li, X.,Li, J.,Rao, Z.
Molecular basis for the inhibition of beta-hydroxyacyl-ACP dehydratase HadAB complex from Mycobacterium tuberculosis by flavonoid inhibitors.
Protein Cell, 6:504-517, 2015

PubMed Abstract: Dehydration is one of the key steps in the biosynthesis of mycolic acids and is vital to the growth of Mycobacterium tuberculosis (Mtb). Consequently, stalling dehydration cures tuberculosis (TB). Clinically used anti-TB drugs like thiacetazone (TAC) and isoxyl (ISO) as well as flavonoids inhibit the enzyme activity of the β-hydroxyacyl-ACP dehydratase HadAB complex. How this inhibition is exerted, has remained an enigma for years. Here, we describe the first crystal structures of the MtbHadAB complex bound with flavonoid inhibitor butein, 2',4,4'-trihydroxychalcone or fisetin. Despite sharing no sequence identity from Blast, HadA and HadB adopt a very similar hotdog fold. HadA forms a tight dimer with HadB in which the proteins are sitting side-by-side, but are oriented anti-parallel. While HadB contributes the catalytically critical His-Asp dyad, HadA binds the fatty acid substrate in a long channel. The atypical double hotdog fold with a single active site formed by MtbHadAB gives rise to a long, narrow cavity that vertically traverses the fatty acid binding channel. At the base of this cavity lies Cys61, which upon mutation to Ser confers drug-resistance in TB patients. We show that inhibitors bind in this cavity and protrude into the substrate binding channel. Thus, inhibitors of MtbHadAB exert their effect by occluding substrate from the active site. The unveiling of this mechanism of inhibition paves the way for accelerating development of next generation of anti-TB drugs.

PubMed: 26081470
DOI: 10.1007/s13238-015-0181-1

Experimental method

X-RAY DIFFRACTION (2.196 Å)