The Chloride Effect in Human Haemoglobin

Perutz, M. F.; Shih, Daniel Tzu-Bi; Williamson, D.

doi:10.1006/jmbi.1994.1394

Cited by 125 publications

(68 citation statements)

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“…An important binding site for chloride, which is also a physiological regulator (3, 14 -18), is at the other end between the two ␣-chains. A second important chloride site was recently discovered between these two regions in the middle of the central dyad axis (19,20). To identify it, "random" (in contrast to "specific") chemical modification was developed where the objective was to react minimally all sites having a common functional feature (e.g.…”

Section: Anions In Central Cavity Of Tetramermentioning

confidence: 99%

Normal and Abnormal Protein Subunit Interactions in Hemoglobins

Manning

Dumoulin

et al. 1998

Journal of Biological Chemistry

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The characteristic properties of hemoglobin are due to the manner in which its individual subunits bond to one another first as an ␣␤ dimer and then as an ␣ 2 ␤ 2 tetramer. These subunit interactions also control the binding of allosteric regulatory molecules because of sites they create as they interact with one another. Some of these interactions in hemoglobin change in the transition between its tetrameric oxy (R, for "relaxed") or deoxy (T, for "tense") conformational states; adult human hemoglobin A (␣ 2 ␤ 2 ) functions as the physiological carrier of O 2 between the arterial and the venous circulation in these two conformations, respectively. The transition between these quaternary states is accompanied by concerted changes in the tertiary structure of the individual subunits upon O 2 binding known as cooperativity, which is responsible for the sigmoidal shape of the O 2 equilibrium curve (1-3). Myoglobin delivers O 2 during muscle contraction, as described in a recent minireview (4), and it has a hyperbolic O 2 equilibrium profile, i.e. no cooperative interactions because it is a single subunit protein. In tetrameric hemoglobin certain sites between the subunits at the quaternary level have the precise geometry or chemical reactivity to bind 2,3-diphosphoglycerate (2,3-DPG), 1 protons, and chloride preferentially to the deoxy conformational state and hence shift the equilibrium away from the oxy conformation, thereby favoring O 2 release. In each quaternary tetramer the oxy and deoxy dimer pairs interact differently to form the two types of tetramer-dimer interfaces in the R and T states. The strength of these interactions influences O 2 binding or release in these respective states and determines how easily the tetramer dissociates to dimers. In human Hb, dimers themselves are held together by strong interactions between their ␣-and ␤-subunits that do not differ significantly for the two R and T conformations.

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Section: Anions In Central Cavity Of Tetramermentioning

confidence: 99%

Normal and Abnormal Protein Subunit Interactions in Hemoglobins

Manning

Dumoulin

et al. 1998

Journal of Biological Chemistry

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“…The oxygen affinity of hemoglobin is further modulated by several non-heme ligands such as protons (3), chloride ions (4,5), and 2,3-disphosphoglycerate (6, 7) that reduce the oxygen affinity by preferentially binding to hemoglobin in the T-state. Besides these natural allosteric effectors, a variety of synthetic molecules has been examined for their capability of lowering the oxygen affinity of hemoglobin, because such allosteric modulators are potentially useful for both research and therapeutic applications (8 -10).…”

mentioning

confidence: 99%

Crystal Structure of Horse Carbonmonoxyhemoglobin-Bezafibrate Complex at 1.55-Å Resolution

Shibayama¹,

Miura²,

Tame³

et al. 2002

Journal of Biological Chemistry

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Bezafibrate, an antilipidemic drug, is known as a potent allosteric effector of hemoglobin. The previously proposed mechanism for the allosteric potency of this drug was that it stabilizes and constrains the T-state of hemoglobin by specifically binding to the large central cavity of the T-state. Here we report a new allosteric binding site of fully liganded R-state hemoglobin for this drug. The high resolution crystal structure of horse carbonmonoxyhemoglobin in complex with bezafibrate reveals that the bezafibrate molecule lies near the surface of the E-helix of each ␣ subunit and the complex maintains the quaternary structure of the R-state. Binding is caused by the close fit of bezafibrate into the binding pocket, which is composed of some hydrophobic residues and the heme edge, suggesting the importance of hydrophobic interactions. Upon binding of bezafibrate, the distance between Fe and the N⑀ 2 of distal His E7(␣58) is shortened by 0.22 Å in the ␣ subunit, whereas no significant structural changes are transmitted to the ␤ subunit. Oxygen equilibrium studies of R-state-locked hemoglobin with bezafibrate in a wet porous sol-gel indicate that bezafibrate selectively lowers the oxygen affinity of one type of subunit within the R-state, consistent with the structural data. These results disclose a new allosteric mechanism of bezafibrate and offer the first demonstration of how the allosteric effector interacts with R-state hemoglobin.

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“…Chloride Effects-In human Hb, Cl Ϫ may act either by neutralizing the positive charges in the central cavity without binding to specific residues (56) or bind at specific sites (57). Two major sites generally considered to be implicated in chloride binding in human Hb are Val-NA1(␣l) that interacts with Ser-H14(␣131) and Lys-EF6(␤82) that interacts with Val-NA1(␤l) (cf.…”

Section: His-na2(␤2) In Hbmentioning

confidence: 99%