7PIV: Melanocortin receptor 4

Active Melanocortin-4 receptor (MC4R)- Gs protein complex bound to agonist NDP-alpha-MSH at 2.86 A resolution. Determined by electron microscopy at 2.86 Å resolution. Released 17 Nov 2021.

Method: Electron microscopy
Resolution: 2.86 Å
Organisms: Homo sapiens, synthetic construct, Rattus norvegicus
Chains: 6
Atoms: 7,814
Mol. weight: 145 kDa
Ligands: CA
Released: 17 Nov 2021

Explore 7PIV in 3D Show helices and sheets RCSB PDB PDBe

Secondary structure: helices and β-sheets

7PIV contains 27 α-helices and 48 β-strands across 5 chains. Residue ranges use author residue numbering, as in the PDB file, from PDBe. To see them in 3D, choose the Cartoon representation with Secondary structure coloring: helices, sheets and coils get different colors.

Chain A: 7 helices, 6 β-strands

Element	Residues	Length	Sheet
α-helix	14-39	26
β-strand	41-46	6	1
β-strand	195-199	5	1
β-strand	204-209	6	1
α-helix	220-223	4
β-strand	229-235	7	1
α-helix	251-264	14
β-strand	272-278	7	1
α-helix	294-297	4
α-helix	299-303	5
α-helix	323-337	15
β-strand	345-349	5	1
α-helix	357-376	20

Chain B: 4 helices, 30 β-strands

Element	Residues	Length	Sheet
α-helix	4-25	22
α-helix	30-33	4
α-helix	34-36	3
β-strand	47-52	6	2
β-strand	58-63	6	3
β-strand	69-74	6	3
β-strand	78-83	6	3
β-strand	89-94	6	3
α-helix	95	1
β-strand	100-105	6	4
β-strand	111-116	6	4
β-strand	121-125	5	4
β-strand	134-139	6	4
β-strand	146-151	6	5
β-strand	156-161	6	5
β-strand	165-170	6	5
β-strand	175-181	7	5
β-strand	187-192	6	6
β-strand	198-203	6	6
β-strand	207-212	6	6
β-strand	218-223	6	6
β-strand	229-234	6	7
β-strand	240-245	6	7
β-strand	250-254	5	7
β-strand	259-264	6	7
β-strand	273	1	8
β-strand	277-278	2	9
β-strand	284-286	3	9
β-strand	289	1	8
β-strand	294-298	5	9
β-strand	304-308	5	9
β-strand	315-320	6	2
β-strand	327-331	5	2
β-strand	335-339	5	2

Chain G: 3 helices, 0 β-strands

Element	Residues	Length
α-helix	10-23	14
α-helix	30-43	14
α-helix	53-55	3

Chain N: 2 helices, 12 β-strands

Element	Residues	Length	Sheet
β-strand	3-7	5	10
β-strand	11-12	2	11
β-strand	18-25	8	10
α-helix	29-31	3
β-strand	34-39	6	12
β-strand	46-51	6	12
β-strand	58-60	3	12
β-strand	68-73	6	10
β-strand	78-83	6	10
α-helix	88-90	3
β-strand	92-98	7	12
β-strand	118	1	12
β-strand	122-124	3	12
β-strand	125-126	2	11

Chain R: 11 helices, 0 β-strands

Element	Residues	Length
α-helix	48-70	23
α-helix	78-107	30
α-helix	119-152	34
α-helix	157-160	4
α-helix	163-186	24
α-helix	192-225	34
α-helix	241-270	30
α-helix	275-281	7
α-helix	284-298	15
α-helix	299-303	5
α-helix	307-315	9

Molecules and chains

Molecule	Chains	Type	Length	Organism	UniProt
Melanocortin receptor 4	R	protein	346	Homo sapiens	P32245 (AlphaFold model)
NDP-alpha-MSH (other names Afamelanotide; Scenesse)	P	protein	15	synthetic construct	P01189 (AlphaFold model)
Isoform Gnas-2 of Guanine nucleotide-binding protein G(s) subunit alpha isoforms short	A	protein	380	Homo sapiens	P63092 (AlphaFold model)
Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1	B	protein	345	Rattus norvegicus	P54311 (AlphaFold model)
Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2	G	protein	71	Mus musculus	P63213
Camelid antibody VHH fragment - nanobody 35	N	protein	134	Lama glama

Sequence of entity 1 (R), FASTA

>7PIV_1 Melanocortin receptor 4 (chains R)
DYKDDDDKMVNSTHRGMHTSLHLWNRSSYRLHSNASESLGKGYSDGGCYEQLFVSPEVFV
TLGVISLLENILVIVAIAKNKNLHSPMYFFICSLAVADMLVSVSNGSETIVITLLNSTDT
DAQSFTVNIDNVIDSVICSSLLASICSLLSIAVDRYFTIFYALQYHNIMTVKRVGIIISC
IWAACTVSGILFIIYSDSSAVIICLITMFFTMLALMASLYVHMFLMARLHIKRIAVLPGT
GAIRQGANMKGAITLTILIGVFVVCWAPFFLHLIFYISCPQNPYCVCFMSHFNLYLILIM
CNSIIDPLIYALRSQELRKTFKEIICCYPLGGLCDLSSRYLEVLFQ

Sequence of entity 2 (P), FASTA

>7PIV_2 NDP-alpha-MSH (other names Afamelanotide; Scenesse) (chains P)
XSYSLEHFRWGKPVX

Sequence of entity 3 (A), FASTA

>7PIV_3 Isoform Gnas-2 of Guanine nucleotide-binding protein G(s) subunit alpha isoforms short (chains A)
MGCLGNSKTEDQRNEEKAQREANKKIEKQLQKDKQVYRATHRLLLLGAGESGKSTIVKQM
RILHVNGFNGDSEKATKVQDIKNNLKEAIETIVAAMSNLVPPVELANPENQFRVDYILSV
MNVPDFDFPPEFYEHAKALWEDEGVRACYERSNEYQLIDCAQYFLDKIDVIKQADYVPSD
QDLLRCRVLTSGIFETKFQVDKVNFHMFDVGGQRDERRKWIQCFNDVTAIIFVVASSSYN
MVIREDNQTNRLQEALNLFKSIWNNRWLRTISVILFLNKQDLLAEKVLAGKSKIEDYFPE
FARYTTPEDATPEPGEDPRVTRAKYFIRDEFLRISTASGDGRHYCYPHFTCAVDTENIRR
VFNDCRDIIQRMHLRQYELL

Sequence of entity 4 (B), FASTA

>7PIV_4 Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 (chains B)
GPGSSGSELDQLRQEAEQLKNQIRDARKACADATLSQITNNIDPVGRIQMRTRRTLRGHL
AKIYAMHWGTDSRLLVSASQDGKLIIWDSYTTNKVHAIPLRSSWVMTCAYAPSGNYVACG
GLDNICSIYNLKTREGNVRVSRELAGHTGYLSCCRFLDDNQIVTSSGDTTCALWDIETGQ
QTTTFTGHTGDVMSLSLAPDTRLFVSGACDASAKLWDVREGMCRQTFTGHESDINAICFF
PNGNAFATGSDDATCRLFDLRADQELMTYSHDNIICGITSVSFSKSGRLLLAGYDDFNCN
VWDALKADRAGVLAGHDNRVSCLGVTDDGMAVATGSWDSFLKIWN

Sequence of entity 5 (G), FASTA

>7PIV_5 Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 (chains G)
MASNNTASIAQARKLVEQLKMEANIDRIKVSKAAADLMAYCEAHAKEDPLLTPVPASENP
FREKKFFCAIL

Sequence of entity 6 (N), FASTA

>7PIV_6 Camelid antibody VHH fragment - nanobody 35 (chains N)
QVQLQESGGGLVQPGGSLRLSCAASGFTFSNYKMNWVRQAPGKGLEWVSDISQSGASISY
TGSVKGRFTISRDNAKNTLYLQMNSLKPEDTAVYYCARCPAPFTRDCFDVTSTTYAYRGQ
GTQVTVSSHHHHHH

Ligands and cofactors

ID	Name	Formula	Copies
CA	Calcium ion	Ca	1

Primary citation

Structures of active melanocortin-4 receptor-Gs-protein complexes with NDP-alpha-MSH and setmelanotide. Heyder, N.A., Kleinau, G., Speck, D. et al. Cell Res (2021) 31:1176-1189. DOI 10.1038/s41422-021-00569-8 · PubMed

Other PDB entries of the same protein (UniProt P32245 (AlphaFold model), which also has an AlphaFold model), best resolution first:

7PIU 2.58 Å, Cryo-EM structure of the agonist setmelanotide bound to the active melanocortin-4…
6W25 2.75 Å, Crystal structure of the Melanocortin-4 Receptor (MC4R) in complex with SHU9119
8WKY 2.9 Å, Crystal structure of the Melanocortin-4 Receptor (MC4R) in complex with S25
7AUE 2.97 Å, Melanocortin receptor 4 (MC4R) Gs protein complex
7F53 3.0 Å, Cryo-EM structure of a-MSH-MC4R-Gs_Nb35 complex
7F54 3.0 Å, Cryo-EM structure of afamelanotide-MC4R-Gs_Nb35 complex
7F55 3.1 Å, Cryo-EM structure of bremelanotide-MC4R-Gs_Nb35 complex
7F58 3.1 Å, Cryo-EM structure of THIQ-MC4R-Gs_Nb35 complex
21LT 3.11 Å, Cryo-EM structure of the setmelanotide-bound human melanocortin receptor 4 (MC4R)-Gq…
9K3K 3.12 Å, Cryo-EM structure of the unliganded human melanocortin receptor 4 (MC4R)-Gs complex
8WKZ 3.3 Å, Crystal structure of the Melanocortin-4 Receptor (MC4R) in complex with S31
8QJ2 3.4 Å, Structure of active state MC4R in complex with a potent ligand mimicking nanobody

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