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. Author manuscript; available in PMC: 2013 Oct 1.
Published in final edited form as: Nat Chem Biol. 2013 Feb 24;9(4):271–276. doi: 10.1038/nchembio.1185

Figure 4. Compound (2) binds selectively to HIF-2α over HIF-1α PAS-B.

Figure 4

(a) Comparison of internal cavity sizes (blue) identified by a 1.4 Å probe within our HIF-2α PAS-B crystal structure (PDB code 3F1P)18 (top) and a homology model of HIF-1α PAS-B domain based on this structure. Sequence differences amongst these two closely related paralogs reduce the expected size of the HIF-1α PAS-B cavity. (b) The HIF-1α PAS-B model suggests that several sequence differences among these paralogs leads to the placement of bulkier side chains (red) within the HIF-1α PAS-B core. These substitutions appear to shrink the cavity observed in HIF-2α PAS-B (HIF-2α PAS-B cavity rendered as a blue surface, superimposed on the HIF-1α PAS-B model). Amino acid differences are indicated with the first designating HIF-2 amino acid identity, and HIF-1 identity by the last letter. (c) ITC measurements of a HIF-1α PAS-B-compound (2) titration does not show detectable protein-ligand interaction under the same conditions used to observe binding with HIF-2α PAS-B (Fig. 1d).