5ZBH
The Crystal Structure of Human Neuropeptide Y Y1 Receptor with BMS-193885
Summary for 5ZBH
| Entry DOI | 10.2210/pdb5zbh/pdb |
| Descriptor | Neuropeptide Y receptor type 1,T4 Lysozyme,Neuropeptide Y receptor type 1, dimethyl 4-{3-[({3-[4-(3-methoxyphenyl)piperidin-1-yl]propyl}carbamoyl)amino]phenyl}-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (2 entities in total) |
| Functional Keywords | g protein-coupled receptor neuropeptide y y1 receptor inhibitor complex structure, signaling protein |
| Biological source | Homo sapiens (Human) More |
| Cellular location | Cell membrane; Multi-pass membrane protein: P25929 |
| Total number of polymer chains | 1 |
| Total formula weight | 61255.73 |
| Authors | |
| Primary citation | Yang, Z.,Han, S.,Keller, M.,Kaiser, A.,Bender, B.J.,Bosse, M.,Burkert, K.,Kogler, L.M.,Wifling, D.,Bernhardt, G.,Plank, N.,Littmann, T.,Schmidt, P.,Yi, C.,Li, B.,Ye, S.,Zhang, R.,Xu, B.,Larhammar, D.,Stevens, R.C.,Huster, D.,Meiler, J.,Zhao, Q.,Beck-Sickinger, A.G.,Buschauer, A.,Wu, B. Structural basis of ligand binding modes at the neuropeptide Y Y1receptor Nature, 556:520-524, 2018 Cited by PubMed Abstract: Neuropeptide Y (NPY) receptors belong to the G-protein-coupled receptor superfamily and have important roles in food intake, anxiety and cancer biology . The NPY-Y receptor system has emerged as one of the most complex networks with three peptide ligands (NPY, peptide YY and pancreatic polypeptide) binding to four receptors in most mammals, namely the Y, Y, Y and Y receptors, with different affinity and selectivity . NPY is the most powerful stimulant of food intake and this effect is primarily mediated by the Y receptor (YR) . A number of peptides and small-molecule compounds have been characterized as YR antagonists and have shown clinical potential in the treatment of obesity , tumour and bone loss . However, their clinical usage has been hampered by low potency and selectivity, poor brain penetration ability or lack of oral bioavailability . Here we report crystal structures of the human YR bound to the two selective antagonists UR-MK299 and BMS-193885 at 2.7 and 3.0 Å resolution, respectively. The structures combined with mutagenesis studies reveal the binding modes of YR to several structurally diverse antagonists and the determinants of ligand selectivity. The YR structure and molecular docking of the endogenous agonist NPY, together with nuclear magnetic resonance, photo-crosslinking and functional studies, provide insights into the binding behaviour of the agonist and for the first time, to our knowledge, determine the interaction of its N terminus with the receptor. These insights into YR can enable structure-based drug discovery that targets NPY receptors. PubMed: 29670288DOI: 10.1038/s41586-018-0046-x PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (3 Å) |
Structure validation
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