Heme-binding site of hemoglobin and myoglobin

The heme-binding site is a critical structural domain within hemoglobin (UniProt P69905, P68871) and myoglobin (UniProt P02144) that houses the iron-protoporphyrin IX prosthetic group (PubChem CID 444098). In hemoglobin, this site enables the cooperative binding and transport of oxygen from the lungs to the rest of the body, while in myoglobin, it functions primarily in oxygen storage and facilitates its diffusion into the mitochondria of muscle cells (StatPearls NBK549815, NBK544256). The iron atom at the center of the heme group must remain in the ferrous (Fe2+) state for effective oxygen binding; its oxidation to the ferric (Fe3+) state leads to the formation of methemoglobin, which is incapable of oxygen transport. This site is a major target for both therapeutic drugs and environmental toxins. For instance, carbon monoxide binds to the heme iron with much higher affinity than oxygen, causing life-threatening hypoxia. Therapeutic agents like voxelotor target the globin structure to allosterically increase oxygen affinity at the heme site, which is beneficial in treating sickle cell disease (FDA Oxbryta Label). Furthermore, antimalarial drugs like chloroquine interfere with the detoxification of heme released during the degradation of hemoglobin by Plasmodium parasites (PubChem CID 2719).

Other names

Heme pocketHeme-binding pocketIron-protoporphyrin IX binding siteGlobin heme site

Drugs and ligands interact with this site through competitive binding at the central iron atom, allosteric stabilization of the protein's oxygenated conformation, or by preventing the sequestration of toxic free heme released during hemoglobin degradation.