9AV9

R2-state HbG-Makassar hemoglobin

Summary for 9AV9

• Entry DOI: 10.2210/pdb9av9/pdb
• Descriptor: Hemoglobin subunit alpha, Hemoglobin subunit beta, GLYCEROL, ... (5 entities in total)
• Functional Keywords: hemoglobin, makassar, sickle, e6a, oxygen transport
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 64891.45

Authors

Feliciano, P.R.,Lee, S.J. (deposition date: 2024-03-01, release date: 2024-12-11, Last modification date: 2025-02-19)

Primary citation

Kostamo, Z.,Ortega, M.A.,Xu, C.,Feliciano, P.R.,Budak, E.,Lam, D.,Winton, V.,Jenkins, R.,Venugopal, A.,Zhang, M.,Jamieson, J.,Coisman, B.,Goldsborough, K.,Hernandez, B.,Kanne, C.K.,Evans, E.N.,Zgodny, J.,Zhang, Y.,Darazim, J.,Patel, A.,Pendergast, M.A.,Manis, J.,Hartigan, A.J.,Ciaramella, G.,Lee, S.J.,Chu, S.H.,Sheehan, V.A.
Base editing HbS to HbG-Makassar improves hemoglobin function supporting its use in sickle cell disease.
Nat Commun, 16:1441-1441, 2025

PubMed Abstract: Adenine base editing can convert sickle hemoglobin (HbS, βΕ6V) to G-Makassar hemoglobin (HbG, βE6A), a naturally occurring variant that is clinically asymptomatic. However, the quality and functionality of purified HbG and of mature HbGG and HbGS red blood cells (RBC) has not been assessed. Here, we develop a mouse model to characterize HbG. Purified HbG appears normal and does not polymerize under hypoxia. The topology of the hemoglobin fold with the βΕ6Α mutation is similar to HbA in the oxy and deoxy states. However, RBC containing HbGS are dehydrated, showing altered function and increased sickling under hypoxia. Blood counts and mitochondrial retention measures place HbGS RBCs as intermediate in severity between HbAS and HbSS, while organ function is comparable to HbAS. HbGG resembles HbAA for most metrics. Our results highlight the importance of functionally assessing the mature red cell environment when evaluating novel gene editing strategies for hematologic disorders.

PubMed: 39920120
DOI: 10.1038/s41467-025-56578-3

Experimental method

X-RAY DIFFRACTION (1.94 Å)