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Disorders Associated with GPRs

Disorders Associated with GPRs. Members: 王建博、秦涛、李中印、王宇. The structural and signal transmit mechanism of the class-C G-protein-coupled receptors. First. What is this? One of the five classes GPCRs How does the GPCRs classified? Based on sequence similarity.

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Disorders Associated with GPRs

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  1. Disorders Associated with GPRs Members:王建博、秦涛、李中印、王宇

  2. The structural and signal transmit mechanism of the class-C G-protein-coupled receptors

  3. First • What is this? One of the five classes GPCRs • How does the GPCRs classified? Based on sequence similarity. class-A:Rhodopsin(视紫红质)-like receptors class-B:secretin(分泌素)-like receptors class-C:mGlu-like receptors

  4. What are class-C GPCRs include? neurotransmitters receptors glutamate(谷氨酸盐) receptors GABA receptors the calcium-sensing receptor sweet taste receptors pheromone(信息素)receptors

  5. Difference • A large extracellular domain——VFTVFT： Venus Flytrap (bilobate双叶形) • Can be regulared by allostericmodulator（变构调节剂） • Dimer ——homo or heter

  6. The structural • Four parts 1.VFT(Venus Flytrap): the agonist binding site 2.CRD(cysteine-rich domain) 3.HD(heptahelicaldomain) C-term

  7. VFT • Tow parts:Lobe-I&Lobe-II • Two conformations： Open(inactive) & Closed(active) antagonist & agonist (抑制剂) (激动剂)

  8. Lobe-I Lobe-II

  9. CRD • The structure and function are unknown • absent CRD:GABA receptor

  10. HD（Heptahelical domain） • Heptahelical • long C-terminal tail • Activity site positive & negative allostericmodulators • independency

  11. How is the signal transduced from one domain to the other?

  12. Class-C GPCRs are constitutive dimers Homodimeric receptors mGlu receptor • A disulfide-linked dimer Cys-residues Lobe-I Lobe-II

  13. Heterodimeric receptors GABAB receptor • Absent disulfide bridge no covalent(共价的) linkage • May have interaction between intracellular tail • ER retention signal (GABAB1)

  14. Activation mechanism of class-C GPCRs interaction between the VFTs

  15. On mGlus receptor • (Roo, resting-open-open) • (Aco, active-closed-open) • (Acc, active-closed-closed) LOGO

  16. Are both Aco & Acc conformations lead to similar properties? • Mutated mGlu VFT composed of two distinct binding sites

  17. Roo, none activity • Aco, half activity • Acc, full activity(Ca2+)

  18. Why? • Roo state: This interface revealed major charge repulsion • Aco state: the interface consists of a number of ionic interactions • Acc state: four acidic side chains are facing each other, creating a cationbinding site

  19. On GABAB receptor • Only have two conformations A signal agonist can fully activate a receptor • Surprisingly GABAB receptor in which GABA binds in the GABAB1 VFT only

  20. But • GABAB2 is necessary for GABAB • only those possessing both the GABAB1 and GABAB2 VFTs display agonist-induced activity • Why Unknown

  21. Allosteric coupling betweenthe extracellular and HD within the dimer

  22. On GABAB receptor HD of GABAB2is a important part • Experiment I • Mutations into either the i2 or i3 loop of GABAB2 suppressed G-protein activation. • The equivalent mutation in GABAB1 had a minor effect

  23. Experiment II • GABAB1 VFT • GABAB2 VFT Demonstrating that the HD of GABAB2possesses enough of the molecular determinants required for G-protein coupling • GABAB2 HD • GABAB2 HD

  24. Experiment III • GABAB2 HD expressed alone can be activated by CGP7930, a positive allosteric modulator of the GABAB receptor. • So.. trans-activation occurs in the GABAB receptor

  25. Another Experiment GABAB1 VFT +GABAB2 HD =can not be activated (GABAB1 VFT + GABAB2 HD) +(GABAB2 VFT + GABAB1 HD) = can be activated In this combination subunits cis-activation occurs • GABAB1 VFT • GABAB2 VFT • GABAB2 HD • GABAB1 HD

  26. In a word, dimer conformation takes a very important part in GABAB receptors

  27. On mGlu receptor • Both cis- and trans-activation occur in mGlu receptors • Because the homodimeric structure

  28. Allosteric functioning of the HD of class C GPCRs

  29. HD can exist in three states HDg states： totally inactive state HD states： Low active efficiency state HD* states： High active efficiency state

  30. HD can be regulared by positive & negative allosteric modulators (变构调节剂)

  31. Allosteric modulators are compounds able to regulate the activity of a receptor by binding at a site distinct from that where endogenous ligands bind

  32. Classification negative allosteric modulators inhibit constitutive activity of the receptor positive allosteric modulators activate the receptor , can enhance either the potency（力量） or the efficacy（效力）, or both

  33. Difference Negative ——directly Positive——indirectly(with agonist)

  34. SO… • the action of negative allosteric modulators is less dependent on the concentration of endogenous ligand(agonist) • But positive allosteric modulators is highly dependent on agonist

  35. Experiment • Bay 7620:negativeallosteric modulators • Ro01-6128: positiveallosteric modulators • EC50 :value of glutamate

  36. Why we intrested in allosteric modulators? Both positive & negative modulators are highly receptor subtype selective. less side effect , long effect Hydrophobic, allowing them to cross the blood brain barrier more easily

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