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The binding site of the PH domain of PDK1 exhibits several structural differences compared to PH domains of other proteins like [http://www.rcsb.org/pdb/protein/Q9UN19?evtc=Suggest&evta=UniProtGene DAPP1] or [http://www.rcsb.org/pdb/protein/P31749?evtc=Suggest&evta=UniProtGene PKBα]. These structural exceptions were described by investigation of Protein-substrate complexes.<ref name="Structural" /> | The binding site of the PH domain of PDK1 exhibits several structural differences compared to PH domains of other proteins like [http://www.rcsb.org/pdb/protein/Q9UN19?evtc=Suggest&evta=UniProtGene DAPP1] or [http://www.rcsb.org/pdb/protein/P31749?evtc=Suggest&evta=UniProtGene PKBα]. These structural exceptions were described by investigation of Protein-substrate complexes.<ref name="Structural" /> | ||
=== | === 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. | 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 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" /> | 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 Ins(1,3,4,5)P<sub>4</sub>-binding pocket a layer of five-ordered water molecules (B-factors) seperate Ins(1,3,4,5)P<sub>4</sub> from the protein (see Fig.2). The water molecules mediate a number of hydrogen bonds from Ins(1,3,4,5)P<sub>4</sub> to the protein. For example binding of the D2-hydroxyl group takes place via an ordered water molecule. But only one of these five water molecules is also conserved in the PH domains of other proteins contacting the D3-phosphate (see Fig.2, coloured yellow).<ref name="Structural" /> | In the PDK1 Ins(1,3,4,5)P<sub>4</sub>-binding pocket a layer of five-ordered water molecules (B-factors) seperate Ins(1,3,4,5)P<sub>4</sub> from the protein (see Fig.2). The water molecules mediate a number of hydrogen bonds from Ins(1,3,4,5)P<sub>4</sub> to the protein. For example binding of the D2-hydroxyl group takes place via an ordered water molecule. But only one of these five water molecules is also conserved in the PH domains of other proteins contacting the D3-phosphate (see Fig.2, coloured yellow).<ref name="Structural" /> | ||
=== Interactions with Phosphatidylinositol Phosphates === | |||