Adult Hemoglobin
(based on 4L7Y.pdb)
T-State adult hemoglobin is shown above in cpk colors.
The backbone image of T-state adult hemoglobin is shown above. Adult hemoglobin (HbA) consists of two subunits α (purple) and two subunits β (tan). Its proximal histidine residues are colored salmon and the heme groups are shown in the cpk color format. It is important for adult hemoglobin to have a lower affinity for oxygen than fetal hemoglobin so that maternal hemoglobin can transfer oxygen across the placenta to fetal hemoglobin.
2,3-bisphosphoglycerate, more commonly known as 2,3-BPG, is an allosteric effector of hemoglobin. 2,3-BPG binds in the central cavity of T-state hemoglobin, stabilizing the T-state and reducing the hemoglobin's oxygen affinity. 2,3-BPG can be a product of glycolysis. Normally, 1,3-BPG is broken down into 3-phosphoglycerate (3-PG) by phosphoglycerate kinase. However, there is an alternative pathway in which 1,3-BPG is converted into 2,3-BPG by bisphosphoglycerate mutase and then 3-PG is formed from 2,3-BPG by 2,3 bisphosphoglycerate phosphatase. A high concentration of carbon dioxide and a low pH increase the activity of bisphosphoglycerate mutase and inhibit 2,3 bisphosphoglycerate phosphatase. This causes an increase in the concentration of 2,3-BPG, which results in hemoglobin releasing oxygen.
2,3-bisphosphoglycerate, more commonly known as 2,3-BPG shown enlarged 3.5 times
2,3-BPG binds to HbA in its central cavity. The negatively charged regions of the BPG molecule (red) bind with the positively charged residues His 2, Lys 82, and His 143 on the β subunits (cyan). The binding of BPG to the hemoglobin helps to stabilize the T-state and reduce hemoglobin's oxygen affinity.

Primary Citations:
Yagami, T., Ballard, B. T., Padovan, J. C., Chait, B. T., Popowicz, A. M., & Manning, J. M. (2002). N-terminal contributions of the beta-subunit of fetal hemoglobin to its tetramer strength: Remote effects at subunit contacts. Protein Science: A Publication of the Protein Society, 11(1), 27-35.
Chen W, Dumoulin A, Li X, Padovan JC, Chait BT, Buonopane R, Platt OS, Manning LR, Manning JM. Transposing sequences between fetal and adult hemoglobins indicates which subunits and regulatory molecule interfaces are functionally related. Biochemistry. 2000 Apr 4;39(13):3774-81. PubMed PMID: 10736177.

    Fetal Hemoglobin
(based on 1FDH.pdb)
T-State fetal hemoglobin is shown above cpk colors.
The backbone image of Fetal hemoglobin (HbF) consists of two α subunits (purple) and γ two subunits (green). Its proximal histidine residues are colored salmon and the heme groups are shown in the cpk color format. It is important for fetal hemoglobin to have a higher affinity for oxygen than adult hemoglobin so that maternal hemoglobin can transfer oxygen across the placenta to fetal hemoglobin.
The higher oxygen affinity of HbF is due to its more stable R-state and its reduced ability to bind with 2,3-BPG in the T-state. The A helix of HbF is responsible for its more stable R-state. More specifically, Gly 1, Glu 5, and Asp 7 on the γ subunits (orange) are the main contributors to the increased tetramer strength of HbF. BPG binds to HbF less than HbA due to the residues Asp 43 (pink) and Ser 143 (cyan) on the γ subunits. Asp 43 prevents the central cavity of the protein from completely opening up in its T-state conformation. This gives BPG less room to bind to the hemoglobin. In HbA, His 143 on the β subunits, a positively charged residue, binds with the negatively charged BPG molecule. In HbF, however, serine is the 143rd residue on the γ subunits (cyan). Serine is a negatively charged residue which will repel the negatively charged BPG molecule. Therefore, BPG is less likely to bind with HbF.