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Originally published in Science Express on 9 May 2002
Science 7 June 2002:
Vol. 296. no. 5574, pp. 1886 - 1889
DOI: 10.1126/science.1073440
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Reports

Structure of an HIF-1alpha -pVHL Complex: Hydroxyproline Recognition in Signaling

Jung-Hyun Min,1 Haifeng Yang,2 Mircea Ivan,2 Frank Gertler,4 William G. Kaelin Jr.,23 Nikola P. Pavletich1*

The ubiquitination of the hypoxia-inducible factor (HIF) by the von Hippel-Lindau tumor suppressor (pVHL) plays a central role in the cellular response to changes in oxygen availability. pVHL binds to HIF only when a conserved proline in HIF is hydroxylated, a modification that is oxygen-dependent. The 1.85 angstrom structure of a 20-residue HIF-1alpha peptide-pVHL-ElonginB-ElonginC complex shows that HIF-1alpha binds to pVHL in an extended beta  strand-like conformation. The hydroxyproline inserts into a gap in the pVHL hydrophobic core, at a site that is a hotspot for tumorigenic mutations, with its 4-hydroxyl group recognized by buried serine and histidine residues. Although the beta  sheet-like interactions contribute to the stability of the complex, the hydroxyproline contacts are central to the strict specificity characteristic of signaling.

1 Cellular Biochemistry and Biophysics Program and Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
2 Dana-Farber Cancer Institute and
3 Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USA.
4 Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
*   To whom correspondence should be addressed. E-mail: nikola{at}xray2.mskcc.org.

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