Database accession: MF7000717
Name: CM14-treated HlyU (Vibrio vulnificus)
PDB ID: 5znx
Experimental method: X-ray (2.11 Å)
Assembly: Homodimer
Source organism: Vibrio vulnificus
Primary publication of the structure:
Lee ZW, Kim BS, Jang KK, Bang YJ, Kim S, Ha NC, Jung YH, Lee HJ, Han HJ, Kim JS, Kim J, Sahu PK, Jeong LS, Kim MH, Choi SH
Small-molecule inhibitor of HlyU attenuates virulence of Vibrio species.
(2019) Sci Rep 9: 4346
PMID: 30867441
Abstract:
Increasing antibiotic resistance has led to the development of new strategies to combat bacterial infection. Anti-virulence strategies that impair virulence of bacterial pathogens are one of the novel approaches with less selective pressure for developing resistance than traditional strategies that impede viability. In this study, a small molecule CM14 [N-(4-oxo-4H-thieno[3,4-c]chromen-3-yl)-3-phenylprop-2-ynamide] that inhibits the activity of HlyU, a transcriptional regulator essential for the virulence of the fulminating human pathogen Vibrio vulnificus, has been identified. Without affecting bacterial growth or triggering the host cell death, CM14 reduces HlyU-dependent expression of virulence genes in V. vulnificus. In addition to the decreased hemolysis of human erythrocytes, CM14 impedes host cell rounding and lysis caused by V. vulnificus. Notably, CM14 significantly enhances survival of mice infected with V. vulnificus by alleviating hepatic and renal dysfunction and systemic inflammation. Biochemical, mass spectrometric, and mutational analyses revealed that CM14 inhibits HlyU from binding to target DNA by covalently modifying Cys30. Remarkably, CM14 decreases the expression of various virulence genes of other Vibrio species and thus attenuates their virulence phenotypes. Together, this molecule could be an anti-virulence agent against HlyU-harboring Vibrio species with a low selective pressure for the emergence of resistance.
Annotations from the GeneOntology database. Only terms that fit at least two of the interacting proteins are shown. Molecular function:
DNA-binding transcription factor activity DNA-binding transcription factor activity
identical protein binding identical protein binding
Biological process: not assigned
Cellular component: not assigned
Structural annotations of the participating protein chains.Entry contents: 2 distinct polypeptide molecules
Chains: A, A-2
Notes: All chains according to the most probable oligomerization state stored in PDBe were considered.
Number of unique protein segments: 1
Name: Transcriptional activator HlyU
Source organism: Vibrio vulnificus
Length: 98 residues
Sequence:Sequence according to the corresponding UniProt protein segmentMNLKDMEQNSAKAVVLLKAMANERRLQILCMLHNQELSVGELCAKLQLSQSALSQHLAWLRRDGLVTTRKEAQTVYYTLKSEEVKAMIKLLHSLYCEE
UniProtKB AC: A0A3Q0L222 (positions: 4-98)
Coverage: 96%
Name: Transcriptional activator HlyU
Source organism: Vibrio vulnificus
Length: 98 residues
Sequence:Sequence according to the corresponding UniProt protein segmentMNLKDMEQNSAKAVVLLKAMANERRLQILCMLHNQELSVGELCAKLQLSQSALSQHLAWLRRDGLVTTRKEAQTVYYTLKSEEVKAMIKLLHSLYCEE
UniProtKB AC: A0A3Q0L222 (positions: 4-98)
Coverage: 96%
Evidence demonstrating that the participating proteins are unstructured prior to the interaction and their folding is coupled to binding. Representative domain in related structures: Winged helix DNA-binding domain (ArsR family) transcriptional regulator
Evidence level: Indirect evidence
Evidence coverage: Only some parts of the structure participates in mutual synergistic folding.
Complex Evidence:
The N-terminal portion of the ArsR family transcriptional regulator, Mj223, is a helix-turn-helix (HTH) winged-helix DNA-binding motif. The C-terminal region of the protein is composed of two leucine-rich α-helices (H5 and H6) that form an antiparallel four-helix bundle with a large, hydrophobic interaction surface on dimerization that forms the hydrophobic core of the dimer (PMID:12471609, PMID:9466913). The C-terminal dimerization subdomain is a nice case of MSF. The protein is a dimer in solution (Dynamic light scattering) (PMID:12471609).
Chain A:
N/A
Chain A-2:
N/A
Surface and contacts features:
Structures from the PDB that contain the same number of proteins, and the proteins from the two structures show a sufficient degree of pairwise similarity, i.e. they belong to the same UniRef90 cluster (the full proteins exhibit at least 90% sequence identity) and convey roughly the same region to their respective interactions (the two regions from the two proteins share a minimum of 70% overlap). Download the CIF file (.cif)
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