Hemoglobin has been a long-standing paradigm for understanding protein allostery. Here, the x-ray structures of two chemically crosslinked, fully liganded hemoglobins, ␣ 2  82 CA 82  and ␣ 2  82 ND 82 , are described at 2.3 Å and 2.6 Å resolution, respectively. Strikingly, these crosslinked hemoglobins assume intermediate conformations that lie between those of R and the controversial liganded hemoglobin state R2 rather than between R and T. Thus, these structures support only a T 7 R 7 R2 allosteric pathway and underscore the physiological importance of the R2 conformation.The quaternary end-state structures of human hemoglobin have long been accepted as the unliganded T and liganded R conformations (1-7). However, the appearance of a second fully liganded conformation, R2 (8-10), has stirred debate as to whether this conformation is an intermediate that lies between T and R (8, 11), an off-pathway structure (12), or the physiologically relevant end state (11, 13). On the basis of the dislocation of the imidazole side chain of residue  2 His-97 from the ␣ 1 C-helix, the R2 conformation was first proposed as an intermediate between the R and T states because it suggested a mechanism by which this residue switches from its T to R state position (8). However, the results of the calculated trajectory of the atomic coordinates in transiting from the T to R2 structure casted doubt on the validity of this proposal (13). Specifically, that trajectory was shown to pass close to the R conformation and thereby suggested R2 might be the physiologically relevant liganded end-state conformation. Clearly, the relevance of the R2 conformation and its position along hemoglobin's allosteric pathway is critical to our complete understanding of the function of hemoglobin. Here, we present the structures of two chemically crosslinked, fully liganded hemoglobins that capture R 7 R2 conformational intermediates and thus clarify the relevance of the R2 state.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.