Structure of fully liganded Hb ζ2β2 strapped in a tense conformation

Martin K. Safo, Tzu Ping Ko, Osheiza Abdulmalik, Zhenning He, Andrew H.J. Wang, Eric R. Schreiter, J. Eric Russell

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)

Abstract

A variant Hb ζ2β2 s that is formed from sickle hemoglobin (Hb S; 2β2 s) by exchanging adult -globin with embryonic ζ-globin subunits shows promise as a therapeutic agent for sickle-cell disease (SCD). Hb ζ2β2s 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 (2β2), Hb ζ2β2 s exhibits atypical properties that include a high oxygen affinity, reduced cooperativity, a weak Bohr effect and blunted 2,3-diphosphoglycerate allostery. Here, the 1.9514;Å resolution crystal structure of human Hb ζ2β2 s that was expressed in complex transgenic knockout mice and purified from their erythrocytes is presented. When fully liganded with carbon monoxide, Hb ζ2β2 s displays a central water cavity, a ζ1-βs2 (or ζ2-βs1) 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 ζ1βs1 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 ζ2β2 s and, moreover, decouples tertiary- and quaternary-structural events that are critical to Hb ligand binding and allosteric function.

Original languageEnglish
Pages (from-to)2061-2071
Number of pages11
JournalActa Crystallographica Section D: Biological Crystallography
Volume69
Issue number10
DOIs
Publication statusPublished - Oct 2013
Externally publishedYes

Keywords

  • 2,3-disphosphoglycerate
  • allostery
  • Bohr effect
  • cooperativity
  • hemoglobin
  • relaxed state
  • tense state

ASJC Scopus subject areas

  • Structural Biology

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