X-ray crystallographic analyses of symmetrical allosteric effectors of hemoglobin: compounds designed to link primary and secondary binding sites

Acta Crystallographica. Section D, Biological Crystallography
M K SafoDonald J Abraham

Abstract

The rational design and X-ray crystallographic analyses of two symmetrical allosteric effectors of hemoglobin (Hb) are reported. Compound design was directed by the previously solved co-crystal structure of one of the most potent allosteric effectors of Hb, 2-[4-[(3,5-dichlorophenylcarbamoyl)-methyl]-phenoxy]-2-methylpropionic acid (RSR4), which revealed two distinct binding sites for this compound in the Hb central water cavity. The primary binding site has been observed for all compounds of this structural class, which stabilize deoxy Hb by engaging in inter-dimer contacts with three of the four protein subunits. Interactions at the secondary binding site of RSR4 occur primarily between the beta(1) and beta(2) subunits and serve to further constrain the deoxy state. Based on these observations, it was hypothesized that compounds with the ability to simultaneously span and link both of these sites would possess increased potency, but at a lower molar concentration than RSR4. Two symmetrical compounds were designed and synthesized based on this hypothesis. The symmetrical effector approach was taken to minimize the number of compound orientations needed to successfully bind at either of the distinct allosteric sites. X-ray crys...Continue Reading

Citations

Mar 5, 2014·Hematology/oncology Clinics of North America·Martin K Safo, Gregory J Kato
Mar 15, 2011·Biochimica Et Biophysica Acta·Martin K SafoTelih Boyiri

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