PDBsum entry 5zbh

Signaling protein

PDB id: 5zbh

Contents

Protein chain

461 a.a.

Ligands

9AF

PDB id:

5zbh

Name:

Signaling protein

Title:

The crystal structure of human neuropeptide y y1 receptor with bms- 193885

Structure:

Neuropeptide y receptor type 1,t4 lysozyme,neuropeptide y receptor type 1. Chain: a. Fragment: unp residues 2-241,unp residues 2-161,unp residues 250-358. Synonym: npy1-r,lysis protein,lysozyme,muramidase,npy1-r. Engineered: yes. Mutation: yes

Source:

Homo sapiens, enterobacteria phage t4t. Human. Organism_taxid: 9606, 857277. Gene: npy1r, npyr, npyy1, e, t4tp126. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108

Resolution:

3.00Å R-factor: 0.224 R-free: 0.251

Authors:

Z.Yang,S.Han,Q.Zhao,B.Wu

Key ref:

Z.Yang et al. (2018). Structural basis of ligand binding modes at the neuropeptide Y Y₁ receptor. Nature, 556, 520-524. PubMed id: 29670288

Date:

11-Feb-18 Release date: 25-Apr-18

Protein chain

P00720  (ENLYS_BPT4) -  Endolysin from Enterobacteria phage T4

Seq: 164 a.a.

Struc: 461 a.a.*

Protein chain

P25929  (NPY1R_HUMAN) -  Neuropeptide Y receptor type 1 from Homo sapiens

Seq: 384 a.a.

Struc: 461 a.a.*

* PDB and UniProt seqs differ at 165 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.3.2.1.17 - lysozyme.
• Reaction: Hydrolysis of the 1,4-beta-linkages between N-acetyl-D-glucosamine and N-acetylmuramic acid in peptidoglycan heteropolymers of the prokaryotes cell walls.

Nature 556:520-524 (2018)

PubMed id: 29670288

Structural basis of ligand binding modes at the neuropeptide Y Y₁ receptor.

Z.Yang, S.Han, M.Keller, A.Kaiser, B.J.Bender, M.Bosse, K.Burkert, L.M.Kögler, D.Wifling, G.Bernhardt, N.Plank, T.Littmann, P.Schmidt, C.Yi, B.Li, S.Ye, R.Zhang, B.Xu, D.Larhammar, R.C.Stevens, D.Huster, J.Meiler, Q.Zhao, A.G.Beck-Sickinger, A.Buschauer, B.Wu.

ABSTRACT

Neuropeptide Y (NPY) receptors belong to the G-protein-coupled receptor superfamily and have important roles in food intake, anxiety and cancer biology ^1,2 . 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 Y₁, Y₂, Y₄ and Y₅ receptors, with different affinity and selectivity ³ . NPY is the most powerful stimulant of food intake and this effect is primarily mediated by the Y₁ receptor (Y₁R) ⁴ . A number of peptides and small-molecule compounds have been characterized as Y₁R antagonists and have shown clinical potential in the treatment of obesity ⁴ , tumour ¹ and bone loss ⁵ . However, their clinical usage has been hampered by low potency and selectivity, poor brain penetration ability or lack of oral bioavailability ⁶ . Here we report crystal structures of the human Y₁R 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 Y₁R to several structurally diverse antagonists and the determinants of ligand selectivity. The Y₁R 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 Y₁R can enable structure-based drug discovery that targets NPY receptors.