Sandbox Reserved 822: Difference between revisions
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=== Interactions with Inositol Phosphates === | === Interactions with Inositol Phosphates === | ||
The structure of the phosphoinositide-binding site of the PDK1 PH domain is unusually spacious. Compared to other PtdIns(3,4,5)P<sub>3</sub>-binding PH domains additional space is present around the D2- and D6-hydroxyl groups, which potentially could accomodate further phosphate groups. This indicates a special affinity of the PDK1 PH domain for inositol phosphates because, physiologically, they are known to be phosphorylated at the D2 and/or D6 position while phosphoinositides, in contrast, do not show modifications at these positions.<ref | The structure of the phosphoinositide-binding site of the PDK1 PH domain is unusually spacious. Compared to other PtdIns(3,4,5)P<sub>3</sub>-binding PH domains additional space is present around the D2- and D6-hydroxyl groups, which potentially could accomodate further phosphate groups. This indicates a special affinity of the PDK1 PH domain for inositol phosphates because, physiologically, they are known to be phosphorylated at the D2 and/or D6 position while phosphoinositides, in contrast, do not show modifications at these positions. The more spacious binding pocket could be an explanation for the ability of the PDK1 PH domain to bind different stereoisomers of phosphoinositides.<ref> PMID: 9445477 </ref> | ||
In the PDK1 PH domain Ins(1,3,4,5)P<sub>4</sub> complex Ins(1,3,4,5)P<sub>4</sub> interacts with protein side chains only. This results in a significantly reduced number of protein-ligand hydrogen bonds (a total of 11) compared to PH domain Ins(1,3,4,5)P<sub>4</sub> complexes of other proteins which form 15 to 16 hydrogen bonds.<ref name="Structural" /> | In the PDK1 PH domain Ins(1,3,4,5)P<sub>4</sub> complex Ins(1,3,4,5)P<sub>4</sub> interacts with protein side chains only. This results in a significantly reduced number of protein-ligand hydrogen bonds (a total of 11) compared to PH domain Ins(1,3,4,5)P<sub>4</sub> complexes of other proteins which form 15 to 16 hydrogen bonds.<ref name="Structural" /> | ||
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=== Interactions with Phosphatidylinositol Phosphates === | === Interactions with Phosphatidylinositol Phosphates === | ||
[[Image:PDK1 PH Domain Interacting With diC4-PtdIns(3,4,5)P3.jpg|left|320px|thumb|Fig.3 Stereo representation of the PDK1 PH domain interacting with diC4-PtdIns(3,4,5)P<sub>3</sub> (marine). Under the semitransparent surface, the conserved Arg residues (green) contacting the D1- and D3- phosphates are drawn as a stick representation.<ref name="Structural" />]] | [[Image:PDK1 PH Domain Interacting With diC4-PtdIns(3,4,5)P3.jpg|left|320px|thumb|Fig.3 Stereo representation of the PDK1 PH domain interacting with diC4-PtdIns(3,4,5)P<sub>3</sub> (marine). Under the semitransparent surface, the conserved Arg residues (green) contacting the D1- and D3- phosphates are drawn as a stick representation.<ref name="Structural" />]] | ||
The interations of the PDK1 PH domain with phosphatidylinositol phosphates were investigated by co-crystallising the PH domain with a PtdIns(3,4,5)P<sub>3</sub> analogue which contains two C4 acyl chains (diC4-PtdIns(3,4,5)P<sub>3</sub>). It was found that <scene name='56/568020/Arg472/1'>Arg472</scene> coordinates the free oxygen atoms on the D1-phosphate whereas the oxygen atom involved in the ester bond to the glycerol does not make any significant contact with the protein. The glycerol backbone itself projects away from the surface of the protein and does not display any other interactions. | |||
