Yonetani Takashi, Tsuneshige Antonio
Department of Biochemistry and Biophysics, Johnson Research Foundation, University of Pennsylvania, Philadelphia, PA 19104-6059, USA.
C R Biol. 2003 Jun;326(6):523-32. doi: 10.1016/s1631-0691(03)00150-1.
Studies of the allosteric mechanism of hemoglobin (Hb) have evolved from phenomenological descriptions to structure-based molecular mechanisms, as the molecular structures of Hb in deoxy and ligated states have been elucidated. The MWC two-state concerted model has been the widely accepted as the most plausible of the allosteric mechanisms of Hb. It assumes that the O2-affinity of Hb is regulated/controlled primarily by the T/R quaternary structural transition and that heterotropic effectors bind preferentially to T (deoxy) Hb to shift the T/R allosteric equilibrium toward the T state. However, recent more comprehensive O2-binding measurements of Hb have revealed a new mechanism, the Global Allostery model. It describes that the O2-affinity and the cooperativity are modulated in greater extents and the Bohr effect is generated primarily by the tertiary structural changes in both T (deoxy) and R (ligated) states of Hb. Differential interactions of heterotropic allosteric effectors with both T (deoxy) and R (ligated) states of Hb induce these tertiary structural changes. The X-ray structure of a complex of R (ligated) Hb with BZF, a potent heterotropic effector, has revealed the stereo-chemical influence of these effectors on the structure of R (ligated) Hb, resulting in the reduction of the ligand affinity in R (ligated) Hb. This model stresses the fundamental importance of the heterotropic interactions in regulation/control of the functionality of Hb. They alter the tertiary structures of both T (deoxy) and R (oxy) Hb, leading to large-scale modulations of the O2 affinity (KT and KR), and consequently the cooperativity (KR/KT) and the Bohr effect (delta P50/delta pH) from a global viewpoint of allostery in Hb.
随着脱氧和结合状态下血红蛋白（Hb）的分子结构得以阐明，对其变构机制的研究已从现象学描述发展到基于结构的分子机制。MWC两态协同模型一直被广泛认为是Hb最合理的变构机制。该模型假定，Hb的氧亲和力主要由T/R四级结构转变调控，且异源效应物优先结合T（脱氧）Hb，从而使T/R变构平衡向T态移动。然而，近期对Hb更全面的氧结合测量揭示了一种新机制——全局变构模型。该模型描述了氧亲和力和协同性在更大程度上受到调节，且玻尔效应主要由Hb的T（脱氧）态和R（结合）态的三级结构变化产生。异源变构效应物与Hb的T（脱氧）态和R（结合）态的差异相互作用诱导了这些三级结构变化。R（结合）Hb与强效异源效应物BZF的复合物的X射线结构揭示了这些效应物对R（结合）Hb结构的立体化学影响，导致R（结合）Hb中配体亲和力降低。该模型强调了异源相互作用在调节/控制Hb功能中的根本重要性。它们改变了T（脱氧）Hb和R（氧合）Hb的三级结构，从Hb变构的全局角度导致氧亲和力（KT和KR）、协同性（KR/KT）和玻尔效应（δP50/δpH）的大规模调节。
