Structure of fully liganded Hb ζ2ß2s trapped in a tense conformation.
Acta Crystallogr D Biol Crystallogr
; 69(Pt 10): 2061-71, 2013 Oct.
Article
em En
| MEDLINE
| ID: mdl-24100324
ABSTRACT
A variant Hb ζ2ß2(s) that is formed from sickle hemoglobin (Hb S; α2ß2(s)) by exchanging adult α-globin with embryonic ζ-globin subunits shows promise as a therapeutic agent for sickle-cell disease (SCD). Hb ζ2ß2(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 (α2ß2), Hb ζ2ß2(s) exhibits atypical properties that include a high oxygen affinity, reduced cooperativity, a weak Bohr effect and blunted 2,3-diphosphoglycerate allostery. Here, the 1.95â
Å resolution crystal structure of human Hb ζ2ß2(s) that was expressed in complex transgenic knockout mice and purified from their erythrocytes is presented. When fully liganded with carbon monoxide, Hb ζ2ß2(s) displays a central water cavity, a ζ1-ß(s)2 (or ζ2-ß(s)1) interface, intersubunit salt-bridge/hydrogen-bond interactions, C-terminal ßHis146 salt-bridge interactions, and a ß-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 ζ1ß(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 ζ2ß2(s) and, moreover, decouples tertiary- and quaternary-structural events that are critical to Hb ligand binding and allosteric function.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Hemoglobina Falciforme
/
Globinas zeta
/
Anemia Falciforme
Tipo de estudo:
Prognostic_studies
Limite:
Adult
/
Animals
/
Humans
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article