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Publication Abstract from PubMed

A variant Hb zeta2beta2(s) that is formed from sickle hemoglobin (Hb S; alpha2beta2(s)) by exchanging adult alpha-globin with embryonic zeta-globin subunits shows promise as a therapeutic agent for sickle-cell disease (SCD). Hb zeta2beta2(s) inhibits the polymerization of deoxygenated Hb S in vitro and reverses characteristic features of SCD in vivo in mouse models of the disorder. When compared with either Hb S or with normal human adult Hb A (alpha2beta2), Hb zeta2beta2(s) exhibits atypical properties that include a high oxygen affinity, reduced cooperativity, a weak Bohr effect and blunted 2,3-diphosphoglycerate allostery. Here, the 1.95 A resolution crystal structure of human Hb zeta2beta2(s) that was expressed in complex transgenic knockout mice and purified from their erythrocytes is presented. When fully liganded with carbon monoxide, Hb zeta2beta2(s) displays a central water cavity, a zeta1-beta(s)2 (or zeta2-beta(s)1) interface, intersubunit salt-bridge/hydrogen-bond interactions, C-terminal betaHis146 salt-bridge interactions, and a beta-cleft, that are highly unusual for a relaxed hemoglobin structure and are more typical of a tense conformation. These quaternary tense-like features contrast with the tertiary relaxed-like conformations of the zeta1beta(s)1 dimer and the CD and FG corners, as well as the overall structures of the heme cavities. This crystallographic study provides insights into the altered oxygen-transport properties of Hb zeta2beta2(s) and, moreover, decouples tertiary- and quaternary-structural events that are critical to Hb ligand binding and allosteric function.

Structure of fully liganded Hb zeta2beta2(s) trapped in a tense conformation.,Safo MK, Ko TP, Abdulmalik O, He Z, Wang AH, Schreiter ER, Russell JE Acta Crystallogr D Biol Crystallogr. 2013 Oct;69(Pt 10):2061-71. doi:, 10.1107/S0907444913019197. Epub 2013 Sep 20. PMID:24100324^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.