Hemoglobin conformational states

The Oxy and Deoxy Forms of Hemoglobin Represent Two Different Conformational States... 

A model for the allosteric behavior of hemoglobin is based on recent observations that oxygen is accessible only to the heme groups of the a-chains when hemoglobin is in the T conformational state. Perutz has pointed out that the heme environment of /3-chains in the T state is virtually inaccessible because of steric hindrance by amino acid residues in the E helix. This hindrance dis-... 

Conformational states. Since P is either a macromolecule such as hemoglobin, or even a relatively small molecule such as succinic acid, it has a very large number of conformations. We shall reduce these to a very few conformations and refer to them as the macrostates, or simply as the states of P. In most cases the ligand will be considered to be in a single macrostate. Only in one case (Section 5.10) we shall allow different conformations for ligand L. 

Figure 6.1. (a) Three different arrangements of four identical subunits linear, square, and tetrahedral. Their corresponding PFs may be constructed from Table 6.1. (b) Schematic description of the distances (in A) between the four subunits of hemoglobin, in two conformational states. 

Linked-function mechanisms for cooperative binding interaction of metabolites and/or drugs, based on the presence of two or more different conformational states of the protein or receptor. See Adair Equation Cooperative Ligand Binding Hemoglobin Hill Equation Plot Koshland-Nemethy-Filmer Model Monod-Wyman-Changeux Model Negative Cooperativity Positive Cooperativity... 

Any polymerization reaction in which the product of each elongation step can itself also undergo further polymerization. When the same types of bonds and/or conformational states that are present in the reactant(s) are generated within product(s) during elongation, the process is referred to as isodesmic polymerization. Such is the case for the indefinite polymerization of actin, tubulin, hemoglobin S, and tobacco mosaic virus coat protein. See Nudeation Protein Polymerization Actin Assembly Kinetics Microtubule Assembly Kinetics Microtubule Assembly Kinetics... 

Fig. 2. Quaternary structural transition in hemoglobin. (A) Subunit motion of hemoglobin in going from the deoxy (or T conformation) to the oxy (or R conformation) state (B) side views of deoxy and oxy states of hemoglobin. In oxy-Hb, the oiiPi dimer is rotated 15° relative to the a2p2 dimer. [Adapted from Dickerson and Geis (1983) illustration copyright by I. Geis],...

Even though in vitro experiments necessarily remove biomolecules from the cellular environment, the structures and dynamics of individual macromolecules provide insights to their biological functions. For example, structural studies have revealed that the protein hemoglobin is made up of four interacting subunits, two a subunits and two ft subunits. Furthermore, each subunit has two distinct conformational states, called the R state and the T state, and the energy of interaction between two neighboring subunits in different states is different from that of two subunits in the same state. This phenomenon is the structural basis of the observed allosteric... 

In studying ET between proteins, complications may arise because the systems exhibit more than one stable conformational state (66). In hemoglobin (Hb), for example, the U2P2 tetramer exists in two distinct states, T (deoxyhemoglobin) and R (oxyhemoglobin). Electron transfer between subunits in hemoglobin hybrids, [ai(Fe), P2(Zn)] and [ai(Zn), p2(Fe)], has been studied by Hoffman and co-workers (47, 66, 121, 151). The association of the Fe and Zn subunits has been extensively characterized (121) photogenerated Zn-protoporphyrin transfers an electron to a ferriheme acceptor, as outlined in Scheme V. 

Addition of substrate, which here is synonymous to the allosteric effector, shifts the equilibrium from the low affinity T-form to the substantially more catalytically active R-form. Since one substrate molecule activates four catalytically active sites, the steep rise in enzyme activity after only a slight increase in substrate concentration is not unexpected. In this model it is important that the RT conformation is not permitted. All subunits must be in the same conformational state at one time to conserve the symmetry of the protomers. The equation given by Hill in 1913, derived from the sigmoidal absorption of oxygen by hemoglobin, is also suitable for a quantitative description of allosteric enzymes with sigmoidal behavior ... 

The existing models of hemoglobin cooperativity differ in taking into consideration different ligational and conformational states. Let us start this discussion with a rather general model introduced by Herzfeld and Stanley (1974). They considered that each subunit may be either ligated or unligated. They then assumed that each subunit may be in either tense (t) or relaxed (r) conformation. Furthermore, at the quaternary level, the whole molecule... 

Reactivity. Hemoglobin can exist ia either of two stmctural coaformatioas, corresponding to the oxy (R, relaxed) or deoxy (T, tense) states. The key differences between these two stmctures are that the constrained T state has a much lower oxygen affinity than the R state and the T state has a lower tendency to dissociate into subunits that can be filtered in the kidneys. Therefore, stabilization of the T conformation would be expected to solve both the oxygen affinity and renal excretion problems. 

Thermodynamically it would be expected that a ligand may not have identical affinity for both receptor conformations. This was an assumption in early formulations of conformational selection. For example, differential affinity for protein conformations was proposed for oxygen binding to hemoglobin [17] and for choline derivatives and nicotinic receptors [18]. Furthermore, assume that these conformations exist in an equilibrium defined by an allosteric constant L (defined as [Ra]/[R-i]) and that a ligand [A] has affinity for both conformations defined by equilibrium association constants Ka and aKa, respectively, for the inactive and active states ... 

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