7XXN

HapR Quadruple mutant, bound to Qstatin

Summary for 7XXN

• Entry DOI: 10.2210/pdb7xxn/pdb
• Descriptor: Hemagglutinin/protease regulatory protein, 1-(5-bromanylthiophen-2-yl)sulfonylpyrazole, GLYCEROL, ... (4 entities in total)
• Functional Keywords: hapr master regulator, transcription
• Biological source: Vibrio cholerae
• Total number of polymer chains: 1
• Total formula weight: 24033.59

Authors

Basu Choudhury, G.,Chaudhari, V.,Ray Chaudhuri, S.,Datta, S. (deposition date: 2022-05-30, release date: 2023-02-22, Last modification date: 2024-11-13)

Primary citation

Sen, H.,Choudhury, G.B.,Pawar, G.,Sharma, Y.,Bhalerao, S.E.,Chaudhari, V.D.,Datta, S.,Raychaudhuri, S.
Diversity in the ligand binding pocket of HapR attributes to its uniqueness towards several inhibitors with respect to other homologues - A structural and molecular perspective.
Int.J.Biol.Macromol., 233:123495-123495, 2023

PubMed Abstract: Vibrio cholerae is a prolific bacterium. Cumulative studies clearly demonstrate the key role of quorum sensing on the lifecycle of this bacterium. Of the sensory network components, HapR is known as high cell density master regulator. Until now, no information is available on native HapR ligand despite the protein having a ligand binding pocket. Interestingly, function of SmcR, a HapR homologue of Vibrio vulnificus is inhibited by a small molecule Qstatin. Structural analysis of SmcR with Qstatin identifies key interacting residues in SmcR ligand binding domain. Despite bearing significant homology with SmcR, HapR function remained unabated by Qstatin. Sequence alignment indicates divergence in the key residues of ligand binding pocket between these two regulators. A series of ligand binding domain mutants of HapR was constructed where only HapR quadruple mutant responded to Qstatin and newly synthesized IMT-VC-212. Crystal structure analysis revealed four key residues are responsible for changes in the volume of ligand binding pocket of HapR quadruple mutant compared to the wild type counterpart, thereby increasing the accessibility of Qstatin and its derivative in case of the former. The mechanistic insights exuberating from this study will remain instrumental in designing inhibitors against wild type HapR.

PubMed: 36739058
DOI: 10.1016/j.ijbiomac.2023.123495

Experimental method

X-RAY DIFFRACTION (2.45 Å)