The high resolution crystal structure of deoxyhemoglobin S

Area of Science:

• Biochemistry
• Structural Biology
• Molecular Medicine

Background:

• Sickle cell disease is caused by a mutation in hemoglobin.
• The polymerization of deoxyhemoglobin S forms sickle cell fibers.
• Understanding the molecular structure of these fibers is key to developing treatments.

Purpose of the Study:

• To refine the crystal structure of deoxyhemoglobin S at high resolution.
• To elucidate the structural basis of hemoglobin tetramer interactions in sickle cell fibers.
• To provide insights for structure-based drug design for sickle cell disease.

Main Methods:

• X-ray crystallography at 2.05 A resolution.
• Refinement of crystal structure using isomorphous crystals.
• Analysis of intermolecular contacts within the deoxyhemoglobin S double strand.

Main Results:

• A refined crystal structure of deoxyhemoglobin S was obtained.
• The double-strand arrangement of hemoglobin tetramers, the building block of sickle cell fibers, was detailed.
• Lateral contacts stabilizing the double strand involve mutant valine interactions, hydrophobic and hydrophilic forces, and bridging water molecules.
• Significant structural differences were observed compared to lower-resolution structures.

Conclusions:

• The refined structure offers detailed insights into the stabilization of the deoxyhemoglobin S double strand.
• This structural information is valuable for understanding hemoglobin polymerization in sickle cell disease.
• The findings may facilitate the structure-based design of novel therapeutic agents.