4ROL: Deoxyhemoglobin In Complex With Imidazolylacryloyl Derivatives

Aromatic aldehydes and ethacrynic acid (ECA) exhibit antipolymerization properties that are beneficial for sickle cell disease therapy. Based on the ECA pharmacophore and its atomic interaction with hemoglobin, we designed and synthesized several compounds - designated as KAUS (imidazolylacryloyl derivatives) - that we hypothesized would bind covalently to betaCys93 of hemoglobin and inhibit sickling. The compounds surprisingly showed weak allosteric and antisickling properties. X-ray studies of hemoglobin in complex with representative KAUS compounds revealed an unanticipated mode of Michael addition between the beta-unsaturated carbon and the N-terminal alphaVal1 nitrogen at the alpha-cleft of hemoglobin, with no observable interaction with betaCys93. Interestingly, the compounds exhibited almost no reactivity with the free amino acids, l-Val, l-His and l-Lys, but showed some reactivity with both glutathione and l-Cys. Our findings provide a molecular level explanation for the compounds biological activities and an important framework for targeted modifications that would yield novel potent antisickling agents.
PDB ID: 4ROLDownload
MMDB ID: 129445
PDB Deposition Date: 2014/10/28
Updated in MMDB: 2015/06
Experimental Method:
x-ray diffraction
Resolution: 1.7  Å
Source Organism:
Similar Structures:
Biological Unit for 4ROL: tetrameric; determined by author and by software (PISA)
Molecular Components in 4ROL
Label Count Molecule
Proteins (4 molecules)
Hemoglobin Subunit Alpha(Gene symbol: HBA1)
Molecule annotation
Hemoglobin Subunit Beta(Gene symbol: HBB)
Molecule annotation
Chemicals (9 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB