Binding of a spin-labeled phenylalanine analog to sickle hemoglobin: EPR and NMR studies |
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Authors: | H Z Lu B L Currie M E Johnson |
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Institution: | Department of Medicinal Chemistry and Pharmacognosy, 545 Pharmacy Building, University of Illinois at Chicago, PO Box 6998, Chicago, IL 60680, USA |
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Abstract: | We have synthesized a spin-label analog of phenylalanine as a competitive inhibitor probe of the sickle hemoglobin aggregation process. Sickle hemoglobin gelation measurements indicate that the spin-label phenylalanine analog is a potent inhibitor of deoxy sickle hemoglobin aggregation. We have also used spin label EPR and high-resolution proton NMR to study the interaction of the phenylalanine analog with hemoglobin, and find that the kinetic off-rate is comparable to, or slower than the hemoglobin rotational rate (i.e., greater than or equal to 10(8) s-1), and that at least one, and perhaps two significant localized interaction region(s) exist within a few angstroms of the beta chain N- and C-termini. Correlation with other known structural information suggests that the observed interaction sites may be relevant to the mechanism for inhibition of sickle hemoglobin aggregation. |
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Keywords: | Hemoglobin Sikle EPR NMR Spin label Competitive binding Hb hemoglobin COHb carbonmonoxy liganded ferrous Hb metHb ferric Hb HbA normal adult Hb HbS sickle Hb Tempone 2 2 6 6-tetrameth-yl-4-oxopiperidone-1-oxyl Phe phenylalanine Cys cysteine Bis-Tris [bis(2-hydroxyethyl)imino]tris(hydroxymethyl)methane |
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