Liganded Hemoglobin Structural Perturbations by the Allosteric Effector L35

¹ Albert Einstein College of Medicine
² Montefiore Medical Center & Albert Einstein College of Medicine

^* To whom correspondence should be addressed. E-mail: rhirsch{at}aecom.yu.edu.

Submitted on May 18, 2004
Revised on July 21, 2004
Accepted on 20 December 2004

	Abstract

Effector binding to liganded hemoglobin (Hb) provides a new understanding of structural determinants of Hb function. L35, a bezafibrate (BZF) related compound, is one of the more potent synthetic regulators of Hb oxygen (O2) affinity. In the presence of IHP and BZF (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 12interface; an R-like structural features within the heme environment; and an intermediate-like state at the central cavity. These long-range structural perturbations appear to stem from L35 specific binding to two classes of binding sites: the central cavity (primarily at the cleft) and the surface. These results indicate that L35 induces allosteric transition species, characterized by domain-specific tertiary and quaternary-like conformation within a global R-quaternary structure.

Key Words: allosteric effector binding, circular dichroism, conformation, front-face fluorescence, hemoglobin, surface plasmon resonance

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