Glycogen Synthase Kinase 3β

Fig 1. GSK3β Signal Transduction Brain Research Reviews 33 (2000) 1-12 Current Opinion in Neurobiology 12 (2002) 275-278

Wnt signal pathway에 작용하는 GSK3ß(Glycogen Synthase Kinase 3β)는 알츠하이머 병(Alzheimer's disease)과 관련이 있는 것으로 알려져 있다. 또한 GSK3β는 미국 버텍스(Vertex) 제약이 Nature : Structure Biology에 발표한 결과에 따르면 혈당(blood glucose)을 조절하는 중요한 역할을 담당하는 것으로 알려지면서 새로운 당뇨병(diabetes) 치료제의 타겟 단백질로도 주목받고 있다.

• Serine / Threonine kinase
• Wnt signal pathway
• Neurodegenerative disease
  • Phosphorylation on TAU protein
  • Related to β-catenin
• Alzheimer’s disease

구조와 기능

Fig 2. Schematic view of GSK3β(1H8F)

• Molecular switches
  • “on” state and “off” state
  • Transferation of the g-phosphate of ATP
    • To the hydroxyl group of serine, threonine, or tyrosine
• Two sub-domain, N lobe and C lobe
  • N lobe: five beta strand and one prominent aC helix
  • C lobe: Helical
  • ATP is bound in a deep cleft between the two lobes
• P Loop
  • Glycine-rich sequence motif (GXGXfG)
  • ATP Binding Loop
• Activation loop and aC helix
  • key regulatory elements
  • Activation loop stabilizes in an open and extended conformation by phosphorylation

알려진 저해제들

* J. Med. Chem., 2003, 46(15); 3333-3341