R state, of hemoglobin

The transition between the T and R states of hemoglobin is also deeply involved in the Bohr effect and cooperativity. Therefore stabilization of either of the two stmctures should diminish these effects, which have important physiologic consequences. The clinical consequences of stabilization are not known. 

Biochemists now know a great deal about the T and R states of hemoglobin, but much remains to be learned about how the T —> R transition occurs. Two models for the cooperative binding of ligands to proteins with multiple binding sites have greatly influenced thinking about this problem. 

A further check was obtained through the study of the effects of alcohols on the oxygen affinity of hemoglobin at various temperatures. This allowed the determination of non bulk-electrostatic contributions, due to the presence of alcohols, to the standard enthalpy and entropy differences between T and R states of hemoglobin. 

CPR can be used to find continuous paths for complex transitions that might have hundreds of saddle points and need to be described by thousands of path points. Examples of such transitions include the quaternary transition between the R and T states of hemoglobin [57] and the reorganization of the retinoic acid receptor upon substrate entry [58]. Because CPR yields the exact saddle points as part of the path, it can also be used in conjunction with nonnal mode analysis to estimate the vibrational entropy of activation... 

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],...

Weissbluth, M. Structural characteristics and electronic states of hemoglobin, in Computational methods for large molecules and localized states in solids (eds. Herman, F., McLean, A. D., Nesbet, R. K.) p. 59, Plenum Press, New York 1973 Weissbluth, M. Hemoglobin, Berlin, Heidelberg, New York, Springer 1974 Mizuhashi, S. J. Phys. Soc. Jpn. 26, 468 (1969)... 

Figure 10.21. Transition from T to R State in Hemoglobin. On oxygenation, one pair of a P subunits shifts with respect to the other by a rotation of 15 degrees.

The quaternary structure observed m the deoxy form of hemoglobin is often referred to as the T (for tense) state because it is quite constrained by subunit—subunit interactions. The quaternary structure of the fully oxygenated form is referred to as the R (for relaxed) state. In light of the observation that the R form of hemoglobin is less constrained, the tense and relaxed designations seem particularly apt. Importantly, in the R state, the... 

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. 

The oxygen affinity of the derivative was shown to be about half that of unmodified hemoglobin under similar conditions, but a degree of cooperativity was preserved. Kquilihrium and kinetic ligand-binding studies on this derivative have been interpreted (62) to show a perturbed R state. It is beheved that although the reaction is between the two P-chains, aP-dimers function independentiy, probably through a flexible connection. 

For many years hemoglobin was the only allosteric protein whose stereochemical mechanism was understood in detail. However, more recently detailed structural information has been obtained for both the R and the T states of several enzymes as well as one genetic repressor system, the trp-repressor, described in Chapter 8. We will here examine the structural differences between the R and the T states of a key enzyme in the glycolytic pathway, phosphofructokinase. 

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