PDBsum entry 6me6

Membrane protein

PDB id: 6me6

Contents

Protein chains

448 a.a.

394 a.a.

Ligands

JEY ×2

OLC

Metals

_ZN

PDB id:

6me6

Name:

Membrane protein

Title:

Xfel crystal structure of human melatonin receptor mt2 in complex with 2-phenylmelatonin

Structure:

Soluble cytochrome b562,melatonin receptor type 1b, rubredoxin. Chain: a, b. Synonym: cytochrome b-562,mel1b receptor,rd,mel1b receptor. Engineered: yes. Mutation: yes

Source:

Escherichia coli, homo sapiens, clostridium pasteurianum. Human. Organism_taxid: 562, 9606, 1501. Gene: cybc, mtnr1b. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108

Resolution:

2.80Å R-factor: 0.220 R-free: 0.249

Authors:

L.C.Johansson,B.Stauch,J.Mccorvy,G.W.Han,N.Patel,A.Batyuk,C.Gati, C.Li,J.Grandner,S.Hao,R.H.J.Olsen,A.R.Tribo,S.Zaare,L.Zhu, N.A.Zatsepin,U.Weierstall,W.Liu,B.L.Roth,V.Katritch,V.Cherezov

Key ref:

L.C.Johansson et al. (2019). XFEL structures of the human MT₂ melatonin receptor reveal the basis of subtype selectivity. Nature, 569, 289-292. PubMed id: 31019305 DOI: 10.1038/s41586-019-1144-0

Date:

05-Sep-18 Release date: 24-Apr-19

Protein chain

P00268  (RUBR_CLOPA) -  Rubredoxin from Clostridium pasteurianum

Seq: 54 a.a.

Struc: 448 a.a.*

Protein chain

P0ABE7  (C562_ECOLX) -  Soluble cytochrome b562 from Escherichia coli

Seq: 128 a.a.

Struc: 448 a.a.*

Protein chain

P49286  (MTR1B_HUMAN) -  Melatonin receptor type 1B from Homo sapiens

Seq: 362 a.a.

Struc: 448 a.a.*

Protein chain

P00268  (RUBR_CLOPA) -  Rubredoxin from Clostridium pasteurianum

Seq: 54 a.a.

Struc: 394 a.a.*

Protein chain

P0ABE7  (C562_ECOLX) -  Soluble cytochrome b562 from Escherichia coli

Seq: 128 a.a.

Struc: 394 a.a.*

Protein chain

P49286  (MTR1B_HUMAN) -  Melatonin receptor type 1B from Homo sapiens

Seq: 362 a.a.

Struc: 394 a.a.*

* PDB and UniProt seqs differ at 161 residue positions (black crosses)

DOI no: 10.1038/s41586-019-1144-0

Nature 569:289-292 (2019)

PubMed id: 31019305

XFEL structures of the human MT₂ melatonin receptor reveal the basis of subtype selectivity.

L.C.Johansson, B.Stauch, J.D.McCorvy, G.W.Han, N.Patel, X.P.Huang, A.Batyuk, C.Gati, S.T.Slocum, C.Li, J.M.Grandner, S.Hao, R.H.J.Olsen, A.R.Tribo, S.Zaare, L.Zhu, N.A.Zatsepin, U.Weierstall, S.Yous, R.C.Stevens, W.Liu, B.L.Roth, V.Katritch, V.Cherezov.

ABSTRACT

The human MT₁ and MT₂ melatonin receptors^1,2 are G-protein-coupled receptors (GPCRs) that help to regulate circadian rhythm and sleep patterns³. Drug development efforts have targeted both receptors for the treatment of insomnia, circadian rhythm and mood disorders, and cancer³, and MT₂ has also been implicated in type 2 diabetes^4,5. Here we report X-ray free electron laser (XFEL) structures of the human MT₂ receptor in complex with the agonists 2-phenylmelatonin (2-PMT) and ramelteon⁶ at resolutions of 2.8 Å and 3.3 Å, respectively, along with two structures of function-related mutants: H208^5.46A (superscripts represent the Ballesteros-Weinstein residue numbering nomenclature⁷) and N86^2.50D, obtained in complex with 2-PMT. Comparison of the structures of MT₂ with a published structure⁸ of MT₁ reveals that, despite conservation of the orthosteric ligand-binding site residues, there are notable conformational variations as well as differences in [³H]melatonin dissociation kinetics that provide insights into the selectivity between melatonin receptor subtypes. A membrane-buried lateral ligand entry channel is observed in both MT₁ and MT₂, but in addition the MT₂ structures reveal a narrow opening towards the solvent in the extracellular part of the receptor. We provide functional and kinetic data that support a prominent role for intramembrane ligand entry in both receptors, and suggest that there might also be an extracellular entry path in MT₂. Our findings contribute to a molecular understanding of melatonin receptor subtype selectivity and ligand access modes, which are essential for the design of highly selective melatonin tool compounds and therapeutic agents.