X-ray Diffraction Study of Binding of 2,3-Diphosphoglycerate to Human Deoxyhaemoglobin

Arnone, A.

doi:10.1038/237146a0

Cited by 733 publications

(294 citation statements)

References 19 publications

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“…The first site identified was that of the natural effector present in red blood cells, 2,3-diphosphoglycerate (DPG), found to bind HbA in a 1:1 stoichiometry [4,5]. It is located at the entrance of the cavity between the two b-subunits that contribute positively charged residues to complement the negatively charged DPG phosphate groups, namely val1, his2 and lys82 of both b chains (Fig.…”

Section: Introductionmentioning

confidence: 99%

R‐state hemoglobin bound to heterotropic effectors: models of the DPG, IHP and RSR13 binding sites

Laberge¹,

Kovesi²,

Yonetani³

et al. 2004

FEBS Letters

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We performed a docking study followed by a 500-ps molecular dynamics simulation of R-state human adult hemoglobin (HbA) complexed to different heterotropic effectors [2,3-diphosphoglycerate (DPG), inositol hexaphosphate (IHP), and 2-[4-[(3,5-dichlorophenylcarbamoyl)-]methyl]-phenoxy]-2-methylpropionic acid (RSR13)) to propose a molecular basis for recently reported interactions of effectors with oxygenated hemoglobin. The simulations were carried out with counterions and explicit solvation. As reported for T-state HbA, the effector binding sites are also located in the central cavity of the R-state and differ depending on effector anionic character. DPG and IHP bind between the a-subunits and the RSR13 site spans the a 1 -, a 2 -and b 2 -subunits. The generated models provide the first report of the molecular details of R-state HbA bound to heterotropic effectors.

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Section: Introductionmentioning

confidence: 99%

R‐state hemoglobin bound to heterotropic effectors: models of the DPG, IHP and RSR13 binding sites

Laberge¹,

Kovesi²,

Yonetani³

et al. 2004

FEBS Letters

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“…Allosteric effectors, 2,3-BPG and IHP, exert a significant effect on the oxygen-binding properties of Hb A. Arnone (4) reported that 2,3-BPG binds to the central cavity of the Hb molecule in the deoxy form, specifically to βVal1, βHis2, βLys82, and βHis143, and thus stabilizes the deoxy quaternary structure and lowers the oxygen affinity. Arnone and Perutz (5) reported that IHP also binds to the central cavity of the deoxy-Hb A molecule, specifically at amino residues βHis2, βLys82, βAsp139, and βHis143.…”

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confidence: 99%

Insights into the Solution Structure of Human Deoxyhemoglobin in the Absence and Presence of an Allosteric Effector

et al. 2007

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We present a nuclear magnetic resonance (NMR) study in solution of the structures of human normal hemoglobin (Hb A) in the deoxy or unligated form in the absence and presence of an allosteric effector, inositol hexaphosphate (IHP), using 15 N-1 H residual dipolar coupling (RDC) measurements. There are several published crystal structures for deoxyhemoglobin A (deoxy-Hb A), and it has been reported that the functional properties of Hb A in single crystals are different from those in solution. Carbonmonoxyhemoglobin A (HbCO A) can also be crystallized in several structures. Our recent RDC studies of HbCO A in the absence and presence of IHP have shown that the solution structure of this Hb molecule is distinctly different from its classical crystal structures (R and R2). In order to have a better understanding of the structure-function relationship of Hb A under physiological conditions, we need to evaluate its structures in both ligated and unligated states in solution. Here, the intrinsic paramagnetic property of deoxy-Hb A has been exploited for the measurement of RDCs using the magnetic-field dependence of the apparent one-bond 1 H-15 N Jcouplings. Our RDC analysis suggests that the quaternary and tertiary structures of deoxy-Hb A in solution differ from its recently determined high-resolution crystal structures. Upon binding of IHP, structural changes in deoxy-Hb A are also observed and these changes are largely within the α 1 β 1 (or α 2 β 2 ) dimer itself. These new structural findings allow us to gain a deeper insight into the structure-function relationship of this interesting allosteric protein.Human normal adult hemoglobin (Hb A), a heterotetrameric protein that transports oxygen from the lungs to tissues, has served as an excellent model for investigating the structurefunction relationship in multimeric, allosteric proteins. Hb A consists of four subunits, i.e., two identical α-chains of 141 amino acid residues each and two identical β-chains of 146 amino acid residues each; each subunit contains a heme group leading to a complex with a molecular weight of ~ 64.5 kDa. The heme iron atom undergoes a spin-state change in going from a highspin paramagnetic Fe +2 (S=2) in the deoxy or unligated form to a diamagnetic Fe +2 (S=0) in the ligated form (with O 2 or CO). The oxygenation of Hb A is regulated by interactions between the O 2 -binding sites (homotropic interactions) and interactions between individual amino acid residues in the protein molecule and various solutes (heterotropic interactions). Heterotropic effectors include hydrogen ions, chloride ions, carbon dioxide, inorganic phosphate ions, and organic phosphate ions [e.g., 2,3-bisphosphoglycerate (2,3-BPG) and inositol hexaphosphate (IHP)] and are known to modulate the oxygen affinity of hemoglobin. For reviews on the NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript structure-function relationship on hemoglobin, see (1-3). Allosteric effectors, 2,3-BPG and IHP, exert a significant effect on the oxygen-binding pr...

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“…It is now well known that both oxy-and deoxyhemoglobin bind organic phosphates . Although the binding sites of deoxyhemoglobin with 2,3-bisphosphoglycerate and Ins-P6 have been determined by X-ray crystallography [8,9], those of oxyhemoglobin have not yet been identified. Organic phosphates increase the acid and alkaline Bohr effect by raising in HbCO and Hb the pK, of some of the weak bases participating in the salt bridges with the phosphate anionic groups [lO,ll].…”

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confidence: 99%

The Interaction of Organic Phosphates with Human and Chicken Hemoglobin

Brygier¹,

Bruin

Hoof

et al. 1975

European Journal of Biochemistry

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In this study the binding properties of inositol hexaphosphate and 2,3‐bisphosphoglycerate to chicken and human deoxyhemoglobin and carboxyhemoglobin were compared. It appeared that in all cases the binding to chicken hemoglobin is much stronger than to human hemoglobin. This is very probably due to the fact that 4 out of the 12 residues, responsible for the binding of phosphates in chicken hemoglobin, are arginines. These are absent in human hemoglobin, where the binding site is made up by only 8 residues. For chicken hemoglobin one strong binding site could be observed in both unliganded and liganded hemoglobin. From these observations we conclude that the same binding site is involved in both the oxy‐ and deoxy structure showing a different affinity to phosphates in the two conformational states. For human hemoglobin we reached the same conclusion.

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X-ray Diffraction Study of Binding of 2,3-Diphosphoglycerate to Human Deoxyhaemoglobin

Cited by 733 publications

References 19 publications

R‐state hemoglobin bound to heterotropic effectors: models of the DPG, IHP and RSR13 binding sites

R‐state hemoglobin bound to heterotropic effectors: models of the DPG, IHP and RSR13 binding sites

Insights into the Solution Structure of Human Deoxyhemoglobin in the Absence and Presence of an Allosteric Effector

The Interaction of Organic Phosphates with Human and Chicken Hemoglobin

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