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The requirement of the PHDs for dioxygen links changes in dioxygen levels with the transcriptional regulation of the gene array that enables the cellular response to chronic hypoxia; the PHDs thus act as an oxygen-sensing component of the HIF system, and their inhibition mimics the hypoxic response. We describe crystal structures of the catalytic domain of human PHD2, an important prolyl-4-hydroxylase in the human hypoxic response in normal cells, in complex with Fe(II) and an inhibitor to 1.7 \u00c5 resolution. PHD2 crystallizes as a homotrimer and contains a double-stranded \u03b2-helix core fold common to the Fe(II) and 2-oxoglutarate-dependant dioxygenase family, the residues of which are well conserved in the three human PHD enzymes (PHD 1\u20133). The structure provides insights into the hypoxic response, helps to rationalize a clinically observed mutation leading to familial erythrocytosis, and will aid in the design of PHD selective inhibitors for the treatment of anemia and ischemic disease.<\/jats:p>","DOI":"10.1073\/pnas.0601283103","type":"journal-article","created":{"date-parts":[[2006,6,16]],"date-time":"2006-06-16T21:16:25Z","timestamp":1150492585000},"page":"9814-9819","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":331,"title":["Cellular oxygen sensing: Crystal structure of hypoxia-inducible factor prolyl hydroxylase (PHD2)"],"prefix":"10.1073","volume":"103","author":[{"given":"Michael A.","family":"McDonough","sequence":"first","affiliation":[{"name":"*Oxford Centre for Molecular Sciences and Department of Chemistry, University of Oxford, Mansfield Road, Oxford OX1 3TA, United Kingdom;"}]},{"given":"Vivian","family":"Li","sequence":"additional","affiliation":[{"name":"Amgen, Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1789"}]},{"given":"Emily","family":"Flashman","sequence":"additional","affiliation":[{"name":"*Oxford Centre for Molecular Sciences and Department of Chemistry, University of Oxford, Mansfield Road, Oxford OX1 3TA, United Kingdom;"}]},{"given":"Rasheduzzaman","family":"Chowdhury","sequence":"additional","affiliation":[{"name":"*Oxford Centre for Molecular Sciences and Department of Chemistry, University of Oxford, Mansfield Road, Oxford OX1 3TA, United Kingdom;"}]},{"given":"Christopher","family":"Mohr","sequence":"additional","affiliation":[{"name":"Amgen, Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1789"}]},{"given":"Beno\u00eet M. 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