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GPCR : ½Å¾à°³¹ßÀÇ µ¹Æı¸

- À§Å° : G Protein Coupled Receptor

G protein : ¿ªÇÒ
1. °¨°¢ Sensory : ÈÄ°¢-400Á¾, ½Ã°¢-3Á¾,  ¹Ì°¢-30¿©Á¾
2. ½Å°æÀü´Þ ¹°Áú ¼ö¿ëü, Cannabinoid
3. chemokine receptors : ¸é¿ª, ¿°Áõ
4. Autonomic nervous system : Ç÷¾Ð, ½ÉÀå¹Úµ¿, ¼ÒÈ­, Æ÷¸¸°¨
5. Cell density sensing
6. Ç×»ó¼º Á¶Àý (e.g., water balance)
7. ½Å¾à °³¹ßÀÇ µ¹Æı¸ : ¾à¹° ÀÛ¿ëÀÇ Àý¹Ý

- Drug design
- Drug screening

ÀÌ·± GPCR´Â »ç¶÷ÀÇ »ý½Ä°ú ´ë»ç, ¸é¿ª, ¿îµ¿, ¼ÒÈ­, È£Èí, Ç÷¾×¼øȯ, ¼ö¸é µî¿¡ Áß¿äÇÑ ¿ªÇÒÀ» ÇÏ¸ç ´Ù¾çÇÑ Áúȯ¿¡ °ü¿©Çϱ⠶§¹®¿¡ Á¦¾à ºÐ¾ß¿¡¼­ ƯÈ÷ Áß¿äÇÏ´Ù. ÁßÃ߽Űæ°è Áúȯ, ½ÉÀå Áúȯ, ¿°Áõ, ´ë»ç ÀÌ»ó µî ´Ù¾çÇÑ Áúº´ Ä¡·á¿¡ ¾²ÀÌ´Â ÆǸżöÀÍ 200À§ ³» ¾à¹°ÀÇ 25% Á¤µµ°¡ GPCR¿Í °ü·ÃµÈ Á¦Ç°ÀÌ´Ù. ´ëÇ¥ÀûÀ¸·Î µÎµå·¯±â µî ¾Ë·¹¸£±â¸¦ Ä¡·áÇÏ´Â Ç×(ù÷)È÷½ºÅ¸¹Î ¾àÇ°À̳ª ¿ì¿ïÁõ Ä¡·áÁ¦ µîÀ» µé ¼ö ÀÖ´Ù.

ÇöÀç °³¹ß ÁßÀÎ ½Å¾àÀÇ 40% ÀÌ»óÀÌ GPCR¿¡ ÃÊÁ¡À» ¸ÂÃß°í ÀÖÀ» ¸¸Å­ Áß¿äÇÑ ¹°Áú

adenosine, bombesin, bradykinin, endothelin, ¥ã-aminobutyric acid (GABA), hepatocyte growth factor (HGF), melanocortins, neuropeptide Y, opioid peptides, opsins, somatostatin, tachykinins, members of the vasoactive intestinal peptide family, and vasopressin;
biogenic amines (e.g., dopamine, epinephrine, norepinephrine, histamine, glutamate, glucagon, acetylcholine (muscarinic effect), and serotonin);
lipid mediators of inflammation (e.g., prostaglandins, prostanoids, platelet-activating factor, and leukotrienes);
and peptide hormones (e.g., calcitonin, C5a anaphylatoxin, follicle-stimulating hormone (FSH), gonadotropin-releasing hormone (GnRH), neurokinin, thyrotropin-releasing hormone (TRH), and oxytocin).




orphan GPCR
GPCRÀº ÀÎüÀÇ ´ëºÎºÐÀÇ »ý¸®Àû È°µ¿¿¡ °ü¿©ÇÏ¸ç ´Ù¾çÇÑ Áúº´Áúȯ°ú °ü·ÃµÇ¾î ÀÖ´Ù. ÆǸżöÀÍ 200À§ ¾È¿¡ 25%ÀÇ ¾àÇ°ÀÌ GPCRÀ» ÀÛ¿ëÁ¡À¸·Î ÇÏ°í ÀÖÀ¸¸ç À̵éÀº ¿¬°£ 270¾ïºÒÀÇ ¸ÅÃâÀ» º¸ÀδÙ. ÀÌµé ¾àÇ°Àº ½ÉÇ÷°üÁúȯ, ¼ÒÈ­±â°üÁúȯ, ÁßÃ߽Űæ°èÁúȯÀ» Æ÷ÇÔÇÑ ´Ù¾çÇÑ Áúº´Áúȯ¿¡ »ç¿ëµÈ´Ù. ¿¹¸¦ µé¾î ºñÁßÃ߽Űæ°è ÁúȯÀ¸·Î Zantac (ranitidine)ÀÌ b2-adrenergic ¼ö¿ëü¸¦ ÅëÇÑ ±Ë¾çÄ¡·á, Cozaar (Losartan)Àº ¾ÈÁö¿ÀÅٽŠ(angiotensin) ¼ö¿ëü¸¦ °æÀ¯ÇÏ¿© °íÇ÷¾ÐÄ¡·á, Claritin (loratadine)ÀÌ Histamin ¼ö¿ëü¸¦ °æÀ¯ÇÏ¿© ¾Ë·¹¸£±â Ä¡·á, Lupron (leuprolide)°¡ GnRH ¼ö¿ëü¸¦ °æÀ¯ÇÏ¿© Àü¸³¼±¾Ï Ä¡·á¿¡ »ç¿ëµÈ´Ù. ÁßÃ߽Űæ°è Áúȯ¿¡´Â Zyprexa (Olnazapine), Risperdal (Risperidone) ÀÌ ¼¼·ÎÅä´Ñ (5-HT) ¼ö¿ëü¸¦ °æÀ¯ÇÏ¿© Á¤½ÅºÐ¿­Áõ Ä¡·á, Neurontin (Gabapentin)Àº GABA ¼ö¿ëü¸¦ °æÀ¯ÇÏ¿© °£Áú Ä¡·á¿¡ »ç¿ëµÈ´Ù. ÀÌ¿Í °°ÀÌ GPCRÀÌ ´Ù¾çÇÑ Áúº´ Áúȯ¿¡ °ü¿©Çϱ⿡ Ç¥Àû GPCR¿¡ ´ëÇÑ Æ¯¼ºÀ» ºÐ¼®ÇÏ°í À̵éÀÇ È°¼ºÀ» Á¶ÀýÇÒ ¼ö ÀÖ´Â ½Å±Ô¹°Áú °³¹ß¿¡ ¸¹Àº Á¦¾àȸ»çµéÀÌ ÅõÀÚÇÏ°í ÀÖ´Ù. ÇöÀç±îÁö ¾à 400 Á¾ÀÇ GPCRÀÌ ¾à¹°ÀÇ ÀÛ¿ëÁ¡ÀÌ µÉ ¼ö ÀÖÀ½ÀÌ ¿¹°ßµÇ°í ÀÖ´Ù. ¶ÇÇÑ GPCR ¸®°£µå´Â ÁÖ·Î ÀÛÀº ºÐÀÚ·Î ÀÌ·ç¾îÁ® ÀÖ¾î ±¸°­Åõ¿©°¡ °¡´ÉÇϰųª ¾à¹° ¼±ÅüºÀ» ³ôÀÏ ¼ö ÀÖ´Â ¸®°£µå º¯ÇüÀÌ ¿ëÀÌÇϴٴ Ư¡À» °¡Áö°í ÀÖ´Ù. ÃÖ±Ù¿¡´Â rhodopsin »ïÂ÷±¸Á¶ ¿¡ ±Ù°ÅÇÑ ÄÄÇ»ÅÍ ½Ã¹Ä·¹À̼ÇÀ» ÅëÇØ ¸®°£µå-¼ö¿ëü°£ÀÇ ºÐÀÚÀû »óÈ£ÀÛ¿ëÀ» °è»êÇÒ ¼ö ÀÖ¾î º¸´Ù È¿°úÀûÀ¸·Î ¾à¹°À» °³¹ßÇÒ ¼ö ÀÖ´Ù.
Àΰ£À¯Àüü»ç¾÷ °á°ú transmitter GPCR·Î ¿¹»óµÇ´Â ¸®°£µå°¡ ¹àÇôÁöÁö ¾ÊÀº GPCRÀÌ 150¿© Á¾ÀÌ ÀÖÀ½ÀÌ ¹àÇôÁ³°í À̸¦ °í¾Æ GPCR (orphan GPCR, oGPCR)À̶ó ÇÑ´Ù. oGPCRÀÇ ¸®°£µå¸¦ ã¾Æ³»´Â °ÍÀº ½Å±Ô »ý¸® È°¼º¹°ÁúÀ» ¹ß±¼ÇÏ´Â °ÍÀ̸ç, À̵éÀº ½Å¾à °³¹ßÀÇ ÁÖ¿ä Ç¥ÀûÀÌ µÈ´Ù. Áö³­ 10¿©³â °£ÀÇ ¿¬±¸°á°ú ¾à 50 ¿©Á¾ÀÇ oGPCR¿¡ ´ëÇÑ ¸®°£µå°¡ ¹àÇôÁö°í, ÇöÀç ¾à 100¿©Á¾ÀÇ Áø¼º oGPCRµéÀÌ ³²¾Æ ÀÖ´Ù. oGPCR¿¡ ´ëÇÑ ¸®°£µå ¹ß±¼¿¬±¸´Â ¿ª¾à¸®ÇÐ (reverse pharmacology)Àû ¹æ¹ýÀÇ °³¼±À» °¡Á® ¿Ô´Ù. ±âÁ¸ÀÇ ÀüÇüÀûÀÎ ¾à¹°°³¹ß ¹æ¹ýÀº Áúº´/ÁúȯÀ» ¼±ÅÃÇÏ°í ±× º´¸®»ý¸®Àû ±âÀüÀ» ÀÌÇØÇÏ¿© À̸¦ Ç¥ÀûÀ¸·Î ¾à¹°À» °³¹ßÇÏ´Â ¹æ¹ýÀ¸·Î½á °á°úÀûÀ¸·Î ±× ¾à¹°ÀÌ GPCRÀ» Ç¥ÀûÀ¸·Î ÇÔÀÌ ¹àÇôÁö°Ô µÈ´Ù. ¹Ý¸é ¿ª¾à¸®ÇÐÀû ¹æ¹ýÀº ±× ¸®°£µå¿Í ±â´ÉÀ» ¸ð¸£´Â GPCRÀÇ ¸®°£µå¸¦ ¸ÕÀú ¹ß±¼ÇÏ°í, À̵éÀÇ ±â´ÉÀ» ¿ªÃßÀûÇÏ¿© ¾î¶°ÇÑ Áúº´/Áúȯ¿¡ ¿¬°üµÇ´Â Áö¸¦ ã´Â °ÍÀÌ´Ù. ¿ª¾à¸®ÇÐÀû ¹æ¹ýÀº ±âÁ¸ÀÇ GPCR ½ÅÈ£Àü´Þ ºÐ¼® ½Ã½ºÅÛÀ» ±âº»À¸·Î ÇÏ¿© »ý¹°Á¤º¸ÇÐ, ÀνǸ®ÄÚ ¾à¹°µðÀÚÀÎ (in silico drug design) ¹æ¹ý ¹× °í¼Ó ½ºÅ©¸®´× ½Ã½ºÅÛÀÌ Àû¿ëµÇ°í ÀÖ´Ù.

(2) ÁöÁú¼º Àü´Þ¹°ÁúÀÇ ºÐÀھฮÇÐ
È£¸£¸ó Áß¿¡´Â ´Ü¹éÁú, ÆéƼµå, ¾Æ¹Î·ùµî È­Çб¸Á¶¿¡ µû¶ó¼­ ¿©·¯Á¾·ù°¡ Àִµ¥ ±× Áß¿¡¼­µµ ÁöÁú¼º ºÐÀÚ¸¦ ¿¬±¸ÀÇ Áß½ÉÀ¸·Î »ï°í ÀÖ´Ù. ÁöÁú¼ºÀ̶õ ¸» ±×´ë·Î Áö¹æó·³ ¹°°ú´Â Àß ¼¯ÀÌÁö ¾Ê´Â ±¸Á¶ÀÇ ¹°ÁúµéÀÌ´Ù.  ÁöÁú¼º Àü´Þ¹°Áú(È£¸£¸ó)¿¡´Â Sphingosine 1-phosphate (S1P)¿Í Lysophosphatidic acid (LPA)°¡ ÀÖ´Ù. À̵éÀÇ ±¸Á¶´Â ÇϱâÀÇ ±×¸²¿¡¼­ º¸´Â °Í°ú °°ÀÌ Àλê±×·ìÀ» °¡Áö°í À־ ¸¶À̳ʽº·Î ÇÏÀüµÈ ºÎºÐ°ú Áö¹æ»êÀÇ ±ä üÀÎÀ¸·Î ±¸¼ºµÇ¾îÁ® ÀÖ´Ù.
À̵éÀÇ »ý¸®Àû º´¸®Àû ±â´É¿¡ ´ëÇÑ ÀÌÇØ°¡ ÀÖ¾î¾ß¸¸ ¾à¹°ÀÇ °³¹ßÀÌ °¡´ÉÇÏ´Ù°í ÇÒ ¼ö ÀÖ´Ù. À̵éÀÇ ÀÛ¿ëÁ¡À¸·Î ¼¼Æ÷¸· ¼ö¿ëüµéÀÌ ÃÖ±Ù ¹àÇôÁ³´Ù. ÃÑ ¿©´ü Á¾ÀÇ ¼ö¿ëü°¡ ¹àÇôÁ³À¸¸ç, 3°³´ÂLPA¿¡ ´ëÇÑ ¼ö¿ëüÀÌ°í ³ª¸ÓÁö ´Ù¼¸ °³´Â S1P¿¡ ´ëÇÑ ¼ö¿ëü·Î ¹àÇôÁ³´Ù. ÀÌµé ¼ö¿ëüµéÀº G´Ü¹éÁú °ø¿ªÇü ¼ö¿ëü¶ó°í ºÐ·ùµÇ´Â ¼ö¿ëüµéÀÇ ÀÏÁ¾ÀÌ´Ù.
¼¼Æ÷¸·À» Åë°úÇÏ´Â ºÎºÐµéÀº ÀÏ·Ä·Î ´Ã¾î¼­ ÀÖ´Â °ÍÀº ¾Æ´Ï¸ç, LPA ¶Ç´Â S1P°¡ °áÇÕÇÒ ¼ö ÀÖ´Â ºÎºÐÀ» ¸¸µé°í ÀÖ´Ù. ÇϱâÀÇ ±×¸²Àº LPAÀÇ ¼ö¿ëüÁß¿¡ Çϳª¸¦ ÄÄÇ»ÅÍ ¸ðµ¨¸µ¿¡ ÀÇÇØ »ïÂ÷¿øÀûÀ¸·Î ³ªÅ¸³½ °ÍÀ¸·Î ¼¼Æ÷ÀÇ ¹Ù±ùÂÊ¿¡¼­ ¼ö¿ëü¸¦ ¹Ù¶óº» ¸ð¾çÀÌ´Ù.
ÀÌµé ¼ö¿ëü¿¡ LPAµîÀÌ °áÇÕÇÏ¸é ¼ö¿ëüÀÇ ±¸Á¶°¡ º¯È­µÇ¾î ÇϱâÀÇ ±×¸²¿¡¼­ º¼ ¼ö ÀÖµíÀÌ ÀÎÁ¢ÇÑ G ´Ü¹éÁúÀÌ È°¼ºÈ­µÇ¸ç, ÀÌ G ´Ü¹éÁúÀº ´Ù½Ã È¿°ú¸¦ Àü´ÞÇØÁÖ´Â È¿¼Òµé(adenylate cyclase, phospholipase C, potasssium channel µî)ÀÇ È°¼ºÀ» Á¶ÀýÇϸç, ÀÌ·¯ÇÑ º¯È­´Â ¼¼Æ÷³»ÀÇ ¿©·¯ ½ÅÈ£Àü´Þ°è(signal transduction)¸¦ ÅëÇÏ¿© ¼¼Æ÷¿¡ µû¶ó¼­ ¼¼Æ÷Áõ½Ä, ºÐÈ­, ¿îµ¿, ¼¼Æ÷»ç¸êµîÀÇ ´Ù¾çÇÑ ¼¼Æ÷¹ÝÀÀÀ» ÀÏÀ¸Å°°Ô µÈ´Ù.
Lysophosphatidylcholine (LPC), Sphingosylphosphorylcholine (SPC), Psychosine À̶ó´Â ÁöÁú¼º ¹°Áú¿¡µµ °ü½ÉÀ» °¡Áö°í ÀÖ´Ù. À̵éÀº LPA¿Í S1PÀÇ ±¸Á¶¿¡ cholineÀÌ ºÙ°Å³ª ÀÎ»ê ´ë½Å¿¡ galactose°¡ °áÇÕÇÑ ±¸Á¶¸¦ °¡Áö°í ÀÖÀ¸¸ç, À̵鿡 ´ëÇÑ ¼ö¿ëü°¡ ¶ÇÇÑ ÃÖ±Ù¿¡ ÁÖ¸ñÀ» ¹Þ°í ÀÖ´Ù. OGR-1, G2A, GPR4, TDAG-8À̶ó´Â 4°³ÀÇ °í¾Æ¼ö¿ëü(Orphan G protein-coupled receptors)°¡ À̵鿡 ´ëÇÑ ¼±ÅÃÀûÀÎ ¼ö¿ëü·Î º¸°íµÇ¾îÀÖ´Ù.

Àΰ£ À¯Àüü »ç¾÷ÀÇ ¿Ï¼ºÀ¸·Î ÈÄ°¢°ú ¹Ì°¢¿¡ °ü¿©ÇÏ´Â GPCRÀ» Á¦¿ÜÇÏ°íµµ ¾à ¼ö¸¹Àº transmitter GPCRµéÀÌ ¹ß°ßµÇ°í ÀÖÀ¸¸ç À̵éÀº ÀÎüÀÇ »ý½Ä ±â´É, ¼ºÀå, ¹°Áú ´ë»ç, Ç×»ó¼º À¯Áö, ½Ä¿å, ¼ö¸é, ½É¸® µî ´ëºÎºÐÀÇ Àΰ£ È°µ¿À» Á¶ÀýÇÑ´Ù. ÀÌ·¯ÇÑ ÀÌÀ¯·Î GPCRÀº Á¦¾à ½ÃÀå¿¡¼­ Áß¿äÇÑ ¾à¹° ÀÛ¿ëÁ¡ÀÌ µÇ°í ÀÖÀ¸¸ç ÇöÀç ½ÃÆǵǴ ¾à¹°µé Áß ÆǸŽÇÀû »óÀ§Á¤µµ°¡ GPCRÀ» ÀÛ¿ëÁ¡À¸·Î ÇÏ°í ÀÖ´Ù. Transmitter GPCR Áß ±× ¸®°£µå¿Í ±â´ÉÀÌ ¹àÇôÁöÁö ¾ÊÀº GPCRµéÀº ¶ÇÇÑ ¼º°øÈ®·üÀÌ ¸Å¿ì ³ôÀº ¾à¹° °³¹ßÀÇ Ç¥ÀûÀÌ µÇ°í ÀÖ´Ù. ±×·¯Çϱ⿡ ¿ì¸®´Â óÀ½ ½ÃÀÛÀÌ ´ÊÀº ¸¸Å­ ¾ÆÁ÷ ½ÃµµµÇÁö ¾ÊÀº ½Å¾à°³¹ßÀ» ´ë»óÀ¸·Î À¯È¿ÇÑ GPCRÀº »õ·Î¿î ¸®°£µå¸¦ ¹àÈ÷±â À§ÇØ ´Ù¾çÇÑ ½ÇÇèÀû ¹æ¹ýµéÀÌ ÀÌ¿ëÀÌ ÇÏ¿©¾ßÇÑ´Ù.
  ¿¹¸¦ µé¸é, ´ëÁß °øÆ÷ÁõÀÌ ÀÖ´Â »ç¶÷µéÀº »ç¶÷µéÀÌ ¸¹Àº Àå¼Ò¿¡¼­ ³ª¼­´Â °ÍÀ» ´ëºÎºÐ ²¨¸®°ÔµÈ´Ù. À̶§ ½Å°æ¾ÈÁ¤Á¦ ¼·ÃëÇÏ¿© ±× »óȲÀ» ±Øº¹ÇÒ ¼ö ÀÖ°Ô µÈ´Ù¸é »ç¶÷µéÀº ±× ¾àÀ» ¸¹ÀÌ ÀÌ¿ëÇÏ°Ô µÉ °ÍÀÌ´Ù.  ÀÌó·³ GPCR ¸®°£µå ¹ß±¼Àº Àΰ£À¯Àüü ÀÌÈÄ ±× ±â´ÉÀ» ¾Ë¾Æ³½´Ù´Â ÀÚü¸¸À¸·Îµµ Á¦¾à »ê¾÷¿¡¼­ ¾öû³­ °æÁ¦Àû È¿°ú¸¦ Áö´Ò ¼ö ÀÖ´Ù.


Approximately 50 GPCRs are estimated to be targeted by nearly half of the currently marketed drugs, and at least 300 GPCRs remain to be exploited2. Intense efforts have been devoted to screening new GPCR ligands that display high potential as drug leads. However, for many GPCRs, such efforts have failed to yield viable drug candidates. Numerous issues prohibit traditional GPCR-targeted drug discovery. For instance, ligands screened by traditional techniques usually act on GPCR orthosteric sites. The conserved characteristics of the orthosteric sites make it difficult to achieve high selectivity for specific GPCR subtypes. Furthermore, the persistent treatment regime of orthosteric ligands often leads to potent side effects and tolerance to the drugs. In addition, for some GPCRs, such as peptide or protein receptors, it is inherently difficult to design synthetic orthosteric ligands. Therefore, the pharmaceutical industry is searching for alternative approaches to identify new modulators of GPCRs. The determination of GPCR structures, mechanisms and ways in which to modulate these properties are therefore of critical importance.

The GPCRs can be classified into five families based on the sequence phylogeny of a conserved heptahelical transmembrane domain (7TM)3. Among these families, class C GPCRs are defined by two unique structural features: first, they possess a large extracellular domain that is distal to the 7TM and contains the orthosteric sites; second, they form constitutive dimers with unique activation modes compared with other classes of GPCRs4. Class C GPCRs are composed of metabotropic glutamate receptors (mGlu receptors), ¥ã-aminobutyric acidB receptors (GABAB receptors), Ca2+-sensing receptors (CaS receptors), sweet and amino acid taste receptors, pheromone receptors, odorant receptors in fish and several orphan receptors3. mGlu, GABAB, and CaS receptors represent an important new class of therapeutic targets that are integral to disorders that affect the central neural system (CNS) and calcium homeostasis4, 5. The taste receptors, on the other hand, attract significant attention from food companies because the taste additives that target these receptors represent a key feature of the large food industry market5.

The recently identified class C GPCRs have been targeted by only two therapeutic drugs currently on the market6. By contrast, in recent years there have been tremendous advances in the discovery of allosteric modulators of class C GPCRs, most likely as a result of the existence of multiple modulation sites for various ligands7. Cinacalcet, one of the first two allosteric modulators of GPCRs on the market, targets the CaS receptor5. This review focuses on the structural features that are involved in ligand recognition by class C GPCRs. The possibilities of modulating receptor function through different types of ligands are then discussed. Finally, representative ligands and the associated sites of four typical family members that contain therapeutic potential are reviewed in detail. The ligands described in this review are small chemical molecules. Peptide ligands, such as antibodies, are not discussed.


ÆäÀ̽ººÏ       ¹æ¸í·Ï      ¼öÁ¤ 2012-10-16 / µî·Ï 2012-10-12 / Á¶È¸ : 21199 (798)



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