Structure of fully liganded Hb ζ2β2s trapped in a tense conformation.

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  • Author(s): Safo MK;Safo MK; Ko TP; Abdulmalik O; He Z; Wang AH; Schreiter ER; Russell JE
  • Source:
    Acta crystallographica. Section D, Biological crystallography [Acta Crystallogr D Biol Crystallogr] 2013 Oct; Vol. 69 (Pt 10), pp. 2061-71. Date of Electronic Publication: 2013 Sep 20.
  • Publication Type:
    Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
  • Language:
    English
  • Additional Information
    • Source:
      Publisher: Wiley-Blackwell Country of Publication: United States NLM ID: 9305878 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1399-0047 (Electronic) Linking ISSN: 09074449 NLM ISO Abbreviation: Acta Crystallogr D Biol Crystallogr Subsets: MEDLINE
    • Publication Information:
      Publication: Malden, MA : Wiley-Blackwell
      Original Publication: Copenhagen : Published for the International Union of Crystallography by Munksgaard, c1993-
    • Subject Terms:
      Anemia, Sickle Cell/*blood ; Anemia, Sickle Cell/*genetics ; Hemoglobin, Sickle/*genetics ; zeta-Globins/*chemistry; Adult ; Allosteric Regulation/genetics ; Animals ; Crystallography, X-Ray ; Genetic Variation ; Hemoglobin, Sickle/metabolism ; Humans ; Ligands ; Mice ; Mice, Knockout ; Mice, Transgenic ; Oxygen/metabolism ; Protein Binding/genetics ; Protein Conformation ; Protein Multimerization/genetics ; alpha-Globins/genetics ; alpha-Globins/metabolism ; zeta-Globins/metabolism
    • Abstract:
      A variant Hb ζ2β2(s) that is formed from sickle hemoglobin (Hb S; α2β2(s)) by exchanging adult α-globin with embryonic ζ-globin subunits shows promise as a therapeutic agent for sickle-cell disease (SCD). Hb ζ2β2(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 (α2β2), 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 1.95 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-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 ζ2β2(s) and, moreover, decouples tertiary- and quaternary-structural events that are critical to Hb ligand binding and allosteric function.
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    • Grant Information:
      5P20RR016439-05 United States RR NCRR NIH HHS; P20 RR016439 United States RR NCRR NIH HHS; HL082754 United States HL NHLBI NIH HHS; K01 HL103186 United States HL NHLBI NIH HHS; R01 HL061399 United States HL NHLBI NIH HHS; HL103186 United States HL NHLBI NIH HHS; HL061399 United States HL NHLBI NIH HHS; P30 CA016059 United States CA NCI NIH HHS; R01 HL082754 United States HL NHLBI NIH HHS; CA16059 United States CA NCI NIH HHS
    • Contributed Indexing:
      Keywords: 2,3-disphosphoglycerate; Bohr effect; allostery; cooperativity; hemoglobin; relaxed state; tense state
    • Molecular Sequence:
      PDB 3W4U
    • Accession Number:
      0 (Hemoglobin, Sickle)
      0 (Ligands)
      0 (alpha-Globins)
      0 (zeta-Globins)
      S88TT14065 (Oxygen)
    • Publication Date:
      Date Created: 20131009 Date Completed: 20140428 Latest Revision: 20240518
    • Publication Date:
      20240518
    • Accession Number:
      PMC3792644
    • Accession Number:
      10.1107/S0907444913019197
    • Accession Number:
      24100324