Paper on 4DKL

Paper for 4DKL: Crystal structure of the m-opioid receptor bound to a morphinan antagonist.

X-ray crustal structure (2.8 angstroms) with a Morphinan antagonist, beta-funan-trexamine (beta-FNA)

beta-FNA covalently attached to K233.

7 TM, 3 Extracellular Loops, 3 Intracellular Loops, TM3-DCL2 Disulfide Bridge C140 (3.25) and C217. R165 (3.50) of the DRY motif forms a salt bridge with D164 (3.49). T279 (6.34) interacts with R165. T279K mutation leads to a constitutively active receptor. The dissociation half-life of the clinically used drug tiotropium at the M3 receptor is 34.7 h and its dissociation constant (Kd) is 40pM. By contrast, the binding pocket for b-FNA in the m-OR is largely exposed to the extracellular surface. This may explain why extremely potent opioids such as buprenorphine, with an inhibition constant (Ki) of 740 pM, diprenorphine (Ki 72 pM), alvimopan (Ki 350 pM) and etorphine (Ki 230 pM) present rapid dissociation half-lives of 44 min, 36 min, 30 min and less than 1 min, respectively.