William Royer, Ph.D.
Academic Role: Professor
Faculty Appointment(s) In:
Biochemistry and Molecular Pharmacology
Figure 1 Legend
Interface water structure in deoxy and liganded Scapharca dimeric hemoglobin (HbI). This figure illustrates the striking disruption of the core interface water structure (depicted as blue spheres) that occurs upon binding ligand (either CO or oxygen). Our experiments have revealed that these water molecules play a key role in mediating intersubunit communication (Royer et al., 1996). Along with the water molecules, a ribbon trace (in red) of both subunits is shown with heme groups (in black) and side chains of Phe 97 and Thr 72 depicted by ball and stick representations (yellow balls for carbon and red balls for oxygen atoms). Upon ligation, by either CO or O2, Phe 97 is extruded from heme pocket into the interface, which disrupts the water cluster. (Coordinates are available from the Protein Data Bank as entry codes 3SDH (deoxy), 4SDH (CO-liganded) and 1HBI (oxygenated) )
Figure 2 Legend
Stereo image of the interface water molecules in deoxy Scapharca dimeric hemoglobin. The water cluster illustrated here plays a critical role in stabilizing the low affinity form Scapharca dimeric hemoglobin. Portions of the E helix (red) and F helix (blue) are shown for each of the two subunits along with bonds (black) for the heme groups and side chains of residues His 69 (distal His), Thr 72, Tyr 75, Asn 79, Lys 96, Phe 97 and His 101 (proximal His). Water molecules are depicted as small light-blue spheres, with likely hydrogen bonds illustrated as dotted lines. Note the multiple hydrogen bonds between water molecules that act to stabilize the water cluster.
Figure 3 Legend
Two depictions of the molecular double strand found in deoxy sickle-cell hemoglobin crystals. In sickle-cell disease, mutation of the 6th residue of the beta (b) subunit from glutamate to valine results in deoxy hemoglobin polymerization into long fibers within the erythrocyte and numerous clinical manifestations. The double strand shown here has been shown by a variety of techniques to be the basic building block of the pathological sickle cell hemoglobin fiber. On the left, the strand is shown as a transparent molecular surface, with heme groups colored red and the mutant valine residues blue. In the representation on the right, the protein backbones are shown as white coils, again with hemes red and mutant valine residues blue. Axial contacts are located between molecules within a single strand in the vertical direction. Lateral contacts involving the blue mutant valine residues act to associate two single strands into a double strand. (PDB entry 2HBS, Harrington et al., 1997).
Figure 4 Legend
Stereo diagram of the lateral contact. The backbone trace for the E and F helices from the acceptor beta (b) subunit of one tetramer is shown in magenta, along with a portion of the A helix (red) and H helix (blue) of the donor beta (b) subunit of the contacting tetramer. The mutant valine is shown in yellow and other important side-chains are shown in black. Likely hydrogen bonds are shown as dashed lines. The mutant valine packs in a hydrophobic pocket formed by Phe 85 (F85), Leu 88 (L88) and Ala 70 in the acceptor subunit. Additionally, a number of water mediated hydrogen bonds are formed at the contact periphery. These detailed interactions provide a template for the design of inhibitors to interfere with polymerization.
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