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Liganded Hemoglobin Structural Perturbations by the Allosteric Effector L35

Qiuying Chen ^*, Iraj Lalezari , Ronald L. Nagel ^*  and Rhoda Elison Hirsch ^* 

^* Department of Medicine, Division of Hematology; Organic Chemistry Laboratory, Division of Immunohematology, Department of Medicine, Montefiore Medical Center; Department of Physiology and Biophysics; and Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, New York

Correspondence: Address reprint requests to Rhoda Elison Hirsch, Tel.: 718-430-3604; Fax: 718-824-3153; E-mail: rhirsch{at}aecom.yu.edu.

Effector binding to liganded hemoglobin (Hb) provides a new understanding of structural determinants of Hb function. L35, a bezafibrate-related compound, is one of the more potent synthetic regulators of Hb oxygen (O₂) affinity. In the presence of inositol hexaphosphate and bezafibrate (or derivatives), liganded Hb at low pH (pH 6.5) exhibits extremely low O₂ affinity and very low cooperativity. In this study, the nature of L35 binding to COHbA at pH 6.35, an altered R-state, is presented. Solution-active site-specific spectroscopic probings by front-face fluorescence and circular dichroism reveal that L35 induces a global heterogeneous conformation in COHbA at pH 6.35 that includes: a T-like structural feature at the 1ß2 interface; an R-like structural feature within the heme environment; and an intermediate-like state at the central cavity. These long-range structural perturbations appear to stem from L35 binding to two classes of binding sites: the central cavity (primarily at the cleft) and the surface. These results indicate that L35 induces an allosteric transition species, characterized by domain-specific tertiary and quaternary-like conformation within a global R-quaternary structure.

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