Open AccessStructure of fully liganded Hb ζ 2 β 2 s trapped in a tense conformation
Author(s) -
Safo Martin K.,
Ko TzuPing,
Abdulmalik Osheiza,
He Zhenning,
Wang Andrew H.J.,
Schreiter Eric R.,
Russell J. Eric
Publication year - 2013
Publication title -
acta crystallographica section d
Language(s) - English
Resource type - Journals
ISSN - 1399-0047
DOI - 10.1107/s0907444913019197
Subject(s) - bohr effect , chemistry , allosteric regulation , cooperativity , hemoglobin , dimer , crystallography , ligand (biochemistry) , heme , salt bridge , stereochemistry , globin , protein quaternary structure , fetal hemoglobin , in vivo , biophysics , receptor , protein subunit , biochemistry , gene , biology , enzyme , genetics , pregnancy , fetus , organic chemistry , mutant , oxygen–haemoglobin dissociation curve
A variant Hb ζ 2 β 2 s that is formed from sickle hemoglobin (Hb S; α 2 β 2 s ) by exchanging adult α‐globin with embryonic ζ‐globin subunits shows promise as a therapeutic agent for sickle‐cell disease (SCD). Hb ζ 2 β 2 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 (α 2 β 2 ), Hb ζ 2 β 2 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 Å resolution crystal structure of human Hb ζ 2 β 2 s that was expressed in complex transgenic knockout mice and purified from their erythrocytes is presented. When fully liganded with carbon monoxide, Hb ζ 2 β 2 s displays a central water cavity, a ζ1–β s 2 (or ζ2–β s 1) interface, intersubunit salt‐bridge/hydrogen‐bond interactions, C‐terminal βHis146 salt‐bridge interactions, and a β‐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 ζ1β 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 ζ 2 β 2 s and, moreover, decouples tertiary‐ and quaternary‐structural events that are critical to Hb ligand binding and allosteric function.