Structure/function of allosteric effectors of hemoglobin

Recently a synthetic hemoglobin allosteric modifier (RSR13) has completed t hree phase I clinical trials and has been advanced into three phase II clin ical trials (brain cancer patients receiving cranial radiation therapy, a t umor oxygenation study, and efficacy in cardiopulmonary bypass surgery). Al losteric modifiers represent a new potential class of therapeutic agents. I nstead of reacting at a specific ligand binding or ligand inhibition site, they bind at alternate sites that regulate the allosteric equilibrium betwe en the low oxygen affinity tense or high oxygen affinity relaxed allosteric states. Detailed oxygen and solution binding experiments combined with x-r ay crystallographic studies on allosteric modifiers of hemoglobin demonstra te that these potential drug agents bind at a new allosteric regulation sit e in hemoglobin. These studies revealed that there were four key effector i nteractions with the protein that provide maximum activity. Two of these mo lecular interactions appear to be directly linked to the regulation of the allosteric equilibrium and explain the observed structure activity. Some of the effecters with similar binding affinities for the same site exhibit va rying degrees of effectiveness, i.e. they possess different intrinsic activ ities. The source of the intrinsic activity appears to be in small differen ces in the positioning of key effector atoms. These results suggest a gener al molecular mechanism for allosteric effector modulation of hemoglobin fun ction that might be of use in other allosteric enzyme or receptor systems.