PDBsum entry 6w25

Membrane protein

PDB id: 6w25

Contents

Protein chain

468 a.a.

Ligands

ACE-NLE-ASP-HIS-4J2-ARG-TRP-LYS-NH2

OLA ×8

Metals

_CA

Waters ×21

PDB id:

6w25

Name:

Membrane protein

Title:

Crystal structure of the melanocortin-4 receptor (mc4r) in complex with shu9119

Structure:

Melanocortin receptor 4,glga glycogen synthase,melanocortin receptor 4. Chain: a. Synonym: mc4-r,glycogen synthase,mc4-r. Engineered: yes. Shu9119. Chain: b. Engineered: yes

Source:

Homo sapiens, pyrococcus abyssi. Human. Organism_taxid: 9606, 272844. Strain: ge5 / orsay. Gene: mc4r, pab2292. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Synthetic: yes. Synthetic construct.

Resolution:

2.75Å R-factor: 0.234 R-free: 0.259

Authors:

J.Yu,L.E.Gimenez,C.C.Hernandez,Y.Wu,A.H.Wein,G.W.Han,K.Mcclary, S.R.Mittal,K.Burdsall,B.Stauch,L.Wu,S.N.Stevens,A.Peisley, S.Y.Williams,V.Chen,G.L.Millhauser,S.Zhao,R.D.Cone,R.C.Stevens

Key ref:

J.Yu et al. (2020). Determination of the melanocortin-4 receptor structure identifies Ca²⁺ as a cofactor for ligand binding. Science, 368, 428-433. PubMed id: 32327598

Date:

04-Mar-20 Release date: 29-Apr-20

Protein chain

P32245  (MC4R_HUMAN) -  Melanocortin receptor 4 from Homo sapiens

Seq: 332 a.a.

Struc: 468 a.a.*

Protein chain

Q9V2J8  (Q9V2J8_PYRAB) -  Glycogen synthase from Pyrococcus abyssi (strain GE5 / Orsay)

Seq: 437 a.a.

Struc: 468 a.a.*

* PDB and UniProt seqs differ at 392 residue positions (black crosses)

Science 368:428-433 (2020)

PubMed id: 32327598

Determination of the melanocortin-4 receptor structure identifies Ca²⁺ as a cofactor for ligand binding.

J.Yu, L.E.Gimenez, C.C.Hernandez, Y.Wu, A.H.Wein, G.W.Han, K.McClary, S.R.Mittal, K.Burdsall, B.Stauch, L.Wu, S.N.Stevens, A.Peisley, S.Y.Williams, V.Chen, G.L.Millhauser, S.Zhao, R.D.Cone, R.C.Stevens.

ABSTRACT

The melanocortin-4 receptor (MC4R) is involved in energy homeostasis and is an important drug target for syndromic obesity. We report the structure of the antagonist SHU9119-bound human MC4R at 2.8-angstrom resolution. Ca²⁺ is identified as a cofactor that is complexed with residues from both the receptor and peptide ligand. Extracellular Ca²⁺ increases the affinity and potency of the endogenous agonist α-melanocyte-stimulating hormone at the MC4R by 37- and 600-fold, respectively. The ability of the MC4R crystallized construct to couple to ion channel Kir7.1, while lacking cyclic adenosine monophosphate stimulation, highlights a heterotrimeric GTP-binding protein (G protein)-independent mechanism for this signaling modality. MC4R is revealed as a structurally divergent G protein-coupled receptor (GPCR), with more similarity to lipidic GPCRs than to the homologous peptidic GPCRs.