Ricerc@Sapienza

I aim at determining the structure of the human CD163(1-5)/Hp(1-1)-Hb ternary complex by single particle cryo-electron microscopy. This complex is involved in hemoglobin clearance and we have obtained this complex in a stable and homogeneous form, providing a sound basis for feasibility of this proposal.
To this day, only the structure of the porcine haptoglobin-hemoglobin complex has been solved, and the third SRCR domain of CD163 has been identified as the key domain interacting with the haptoglobin-hemoglobin complex, however, a detailed structural description of the interaction between hemoglobin, haptoglobin and CD163 still lacks. The size of the human ternary CD163(1-5)/Hp(1-1)-Hb complex (200 kDa) enable its study by single particle cryoEM, which will provide relevant structural insights since these three actors play a key role during physiological and pathological hemolysis, such as malaria and hemoglobinopathies.
Notably, hemoglobin degradation in the liver and accumulation of CD163-expressing macrophages in the vicinity of tumor cells are exploited in drug design and targeting. For instance, Therapure Innovations, a division of Therapure Biopharma Inc. based in Mississauga Canada, has developed TBI 302, a hemoglobin-conjugated floxuridine compound that has already been approved by the Food and Drug Administration for phase-1 clinical trial for liver cancer treatment.
In this context, the structure of the complex gathering haptoglobin-hemoglobin and CD163, their physiological receptor, will be of great value to rationally engineer new hemoglobin conjugates that exploit CD163 as selective access to malignant cells.