3-phosphoinositide-dependent protein kinase 1

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== Function ==
== Function ==
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'''3-phosphoinositide-dependent protein kinase 1''' (Pdk1) activates many other kinases. Pdk1 main effector is protein kinase B (Akt). <scene name='54/542348/Cv/6'>Serine (Ser241 in human) is the Pdk1 phosphorylated residue (PSer)</scene>. Pdk1 is important in signaling pathways activated by growth factors and hormones. It interacts with membrane phospholipids. <ref>PMID:15209375</ref>
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'''3-phosphoinositide-dependent protein kinase 1''' (PDK1) activates many other kinases. PDK1 main effector is protein kinase B (Akt). <scene name='54/542348/Cv/6'>Serine (Ser241 in human) is the PDK1 phosphorylated residue (PSer)</scene>. PDK1 is important in signaling pathways activated by growth factors and hormones. It interacts with membrane phospholipids. <ref>PMID:15209375</ref>
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== Disease ==
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PDK1 is an enzyme that plays a central role in signal transduction pathways involved in cell growth, metabolism, and survival. It belongs to the family of AGC (protein kinase A, G, and C) kinases and is a key regulator of various cellular processes.
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Inhibition of Pdk1 leads to increase in α-secretase activity at the neuronal surface causing cellular prion protein and amyloid precursor protein to be cleaved into their nonpathogenic forms.
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PDK1 is known for its ability to phosphorylate and activate a group of kinases called AGC kinases, which includes protein kinase B (PKB/Akt), protein kinase C (PKC), and serum and glucocorticoid-regulated kinase (SGK), among others. PDK1 phosphorylates a conserved activation loop residue (threonine or serine) of AGC kinases, which leads to their activation and subsequent downstream signaling events.
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== Structural highlights ==
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The activation of PDK1 is tightly regulated and relies on the presence of phosphatidylinositol-3,4,5-trisphosphate (PIP3) or phosphatidylinositol-3,4-bisphosphate (PIP2), which are generated by phosphoinositide 3-kinase (PI3K) signaling. PDK1 contains a pleckstrin homology (PH) domain that specifically binds to these phosphoinositides, allowing its recruitment to the plasma membrane, where it becomes active.
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Pdk1 structure contains 2 domains: kinase (residues 71-359 in human) and PH (residues 459-550) in human). The PH (Plecksin Homology) domain interacts with phospholipids. The kinase domain (kd) contains 3 binding sites. These are for substrate-binding, ATP-binding and allosteric activator docking (PIF - [Pdk1-Interacting Fragment] -pocket). <scene name='54/542348/Cv/7'>Pyrazoloquinazoline inhibitor binding site</scene>. Water molecules shown as red spheres.
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Once activated, PDK1 phosphorylates the AGC kinases on a conserved residue within their activation loop, initiating a signaling cascade that regulates multiple cellular processes. These processes include cell proliferation, growth, survival, metabolism, and cytoskeletal rearrangements.
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== 3D Structures of Pdk1==
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[[Pdk1 3D structures]]
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</StructureSection>
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== 3D Structures of Pdk1==
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Updated on {{REVISIONDAY2}}-{{MONTHNAME|{{REVISIONMONTH}}}}-{{REVISIONYEAR}}
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The dysregulation of PDK1 and its downstream signaling pathways has been implicated in various diseases, including cancer, diabetes, and cardiovascular disorders. Consequently, PDK1 has emerged as a potential therapeutic target for the development of novel drugs aimed at modulating these signaling pathways.
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{{#tree:id=OrganizedByTopic|openlevels=0|
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*Pdk1 kinase domain
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In summary, 3-phosphoinositide-dependent protein kinase 1 (PDK1) is a crucial enzyme involved in the activation of AGC kinases, which regulate a wide range of cellular processes. Its activation is dependent on phosphoinositide signaling, and it serves as a central hub in various signaling pathways involved in cell growth, metabolism, and survival.
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**[[1h1w]] – hPdk1 + PSer – human <br />
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== Disease ==
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**[[1uu3]], [[1uu7]], [[1uu8]], [[1uu9]], [[1uvr]], [[1z5m]], [[2pe0]], [[2pe1]], [[2pe2]], [[3h9o]], [[2xch]], [[2xck]], [[3qcq]], [[3qcs]], [[3qcx]], [[3qcy]], [[3qd0]], [[3qd3]], [[3qd4]], [[3nus]], [[3nuu]], [[3nuy]], [[3nun]], [[3sc1]], [[3rwp]], [[3rwq]], [[5hkm]], [[5hng]], [[5ho7]], [[5ho8]] – hPdk1 + PSer + inhibitor <br />
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**[[3orx]], [[3orz]], [[3otu]], [[3qc4]], [[3rcj]], [[5lvl]], [[4xx9]], [[5ack]] – hPdk1 (mutant) + PSer + inhibitor <br />
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**[[2r7b]], [[3ion]], [[3iop]], [[3nax]], [[3nay]] – hPdk1 + inhibitor <br />
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**[[3pwy]] – hPdk1 (mutant) + inhibitor <br />
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**[[1oky]], [[1okz]] – hPdk1 + PSer + staurosporine <br />
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**[[2biy]], [[3hrc]] – hPdk1 (mutant) + ATP <br />
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**[[4ct1]] – hPdk1 (mutant) + ATP + PSer + PS315<br />
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**[[5lvo]] – hPdk1 (mutant) + ATP + PSer + PSE10<br />
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**[[5lvp]] – hPdk1 (mutant) + ATP + PSer + peptide<br />
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**[[4ct2]] – hPdk1 (mutant) + ATP + PSer <br />
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**[[5lvm]] – hPdk1 (mutant) + adenine + PSer <br />
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**[[5lvn]] – hPdk1 (mutant) + adenosine + PSer <br />
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**[[4rqk]], [[4rqv]], [[5mrd]] – hPdk1 (mutant) + ATP + PSer + inhibitor<br />
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**[[4rrv]] – hPdk1 (mutant) + ATP + PSer + serine/threonine protein kinase N2<br />
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**[[3hrf]], [[4a06]], [[4a07]], [[4aw0]], [[4aw1]] – hPdk1 (mutant) + PSer + ATP + activator<br />
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*Pdk1 PH domain
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Inhibition of PDK1 leads to increase in α-secretase activity at the neuronal surface causing cellular prion protein and amyloid precursor protein to be cleaved into their nonpathogenic forms.
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== Structural highlights ==
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PDK1 structure contains 2 domains: kinase (residues 71-359 in human) and PH (residues 459-550) in human). The PH (Plecksin Homology) domain interacts with phospholipids. The kinase domain (kd) contains 3 binding sites. These are for substrate-binding, ATP-binding and allosteric activator docking (PIF - [PDK1-Interacting Fragment] -pocket). <scene name='54/542348/Cv/7'>Pyrazoloquinazoline inhibitor binding site</scene>. Water molecules shown as red spheres.
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== 3D Structures of PDK1==
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[[Pdk1 3D structures]]
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</StructureSection>
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**[[1w1h]] – hPdkl <br />
 
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**[[2vki]] – hPdk1 (mutant)<br />
 
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**[[1w1d]], [[1w1g]] – hPdk1 + inositol phosphate <br />
 
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}}
 
== References ==
== References ==
<references/>
<references/>
[[Category:Topic Page]]
[[Category:Topic Page]]

Current revision

Human Pdk1 kinase domain containing phosphorylated serine 241 complex with pyrazoloquinazoline inhibitor, sulfate and glycerol (PDB entry 2xch)

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References

  1. ↑ Mora A, Komander D, van Aalten DM, Alessi DR. PDK1, the master regulator of AGC kinase signal transduction. Semin Cell Dev Biol. 2004 Apr;15(2):161-70. PMID:15209375

Proteopedia Page Contributors and Editors (what is this?)

Michal Harel, Alexander Berchansky, Joel L. Sussman

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