Buy article online - an online subscription or single-article purchase is required to access this article.
Download citation
Download citation
link to html
A variant Hb ζ2β2s that is formed from sickle hemoglobin (Hb S; α2β2s) by exchanging adult α-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 (α2β2), Hb ζ2β2s 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 ζ2β2s that was expressed in complex transgenic knockout mice and purified from their erythrocytes is presented. When fully liganded with carbon monoxide, Hb ζ2β2s 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 ζ2β2s and, moreover, decouples tertiary- and quaternary-structural events that are critical to Hb ligand binding and allosteric function.

Supporting information

PDB reference: Hb ζ2β2s, 3w4u


Subscribe to Acta Crystallographica Section D: Biological Crystallography

The full text of this article is available to subscribers to the journal.

If you have already registered and are using a computer listed in your registration details, please email support@iucr.org for assistance.

Buy online

You may purchase this article in PDF and/or HTML formats. For purchasers in the European Community who do not have a VAT number, VAT will be added at the local rate. Payments to the IUCr are handled by WorldPay, who will accept payment by credit card in several currencies. To purchase the article, please complete the form below (fields marked * are required), and then click on `Continue'.
E-mail address* 
Repeat e-mail address* 
(for error checking) 

Format*   PDF (US $40)
   HTML (US $40)
   PDF+HTML (US $50)
In order for VAT to be shown for your country javascript needs to be enabled.

VAT number 
(non-UK EC countries only) 
Country* 
 

Terms and conditions of use
Contact us

Follow Acta Cryst. D
Sign up for e-alerts
Follow Acta Cryst. on Twitter
Follow us on facebook
Sign up for RSS feeds