21LT: Setmelanotide

Cryo-EM structure of the setmelanotide-bound human melanocortin receptor 4 (MC4R)-Gq complex. Determined by electron microscopy at 3.11 Å resolution. Released 12 Aug 2026.

Method: Electron microscopy
Resolution: 3.11 Å
Organisms: synthetic construct, Homo sapiens, Rattus norvegicus
Chains: 5
Atoms: 6,748
Mol. weight: 146.51 kDa
Ligands: CA
Released: 12 Aug 2026

Explore 21LT in 3D Show helices and sheets RCSB PDB PDBe

Secondary structure: helices and β-sheets

21LT contains 30 α-helices and 35 β-strands across 4 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: 10 helices, 6 β-strands

Element	Residues	Length	Sheet
α-helix	7-32	26
β-strand	34-39	6	1
α-helix	46-56	11
β-strand	184-191	8	1
β-strand	194-201	8	1
α-helix	211-215	5
β-strand	220-226	7	1
α-helix	233-244	12
α-helix	247-249	3
β-strand	253-259	7	1
α-helix	261-270	10
α-helix	275-278	4
α-helix	280-282	3
α-helix	299-317	19
β-strand	326-329	4	1
α-helix	338-358	21

Chain B: 5 helices, 29 β-strands

Element	Residues	Length	Sheet
α-helix	6-25	20
α-helix	30-33	4
α-helix	34-36	3
β-strand	43	1	2
β-strand	47-51	5	3
β-strand	58-63	6	4
β-strand	69-74	6	4
β-strand	78-83	6	4
β-strand	88-94	7	4
α-helix	95	1
β-strand	100-105	6	5
β-strand	111-116	6	5
β-strand	121-125	5	5
β-strand	134-139	6	5
β-strand	146-153	8	6
β-strand	156-161	6	6
β-strand	166-170	5	6
β-strand	175-180	6	6
β-strand	187-192	6	7
β-strand	198-203	6	7
β-strand	208-212	5	7
β-strand	218-222	5	7
β-strand	229-234	6	8
β-strand	240-245	6	8
β-strand	249-254	6	8
β-strand	259-264	6	8
α-helix	272	1
β-strand	273-278	6	2
β-strand	284-289	6	2
β-strand	294-298	5	2
β-strand	304-307	4	2
β-strand	315-320	6	3
β-strand	327-331	5	3
β-strand	336-339	4	3

Chain G: 3 helices, 0 β-strands

Element	Residues	Length
α-helix	13-23	11
α-helix	30-43	14
α-helix	53-55	3

Chain R: 12 helices, 0 β-strands

Element	Residues	Length
α-helix	48-70	23
α-helix	78-102	25
α-helix	103-107	5
α-helix	118-152	35
α-helix	157-160	4
α-helix	163-186	24
α-helix	191-226	36
α-helix	242-269	28
α-helix	281-283	3
α-helix	284-298	15
α-helix	299-303	5
α-helix	307-314	8

Molecules and chains

Molecule	Chains	Type	Length	Organism	UniProt
Setmelanotide	P	protein	8	synthetic construct
Melanocortin receptor 4,LgBiT subunit	R	protein	505	Homo sapiens, synthetic construct	P32245 (AlphaFold model)
G subunit q (Gi1-Gq chimeric)	A	protein	361	Homo sapiens
Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1,HiBiT	B	protein	371	Rattus norvegicus, synthetic construct	P54311 (AlphaFold model)
Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2	G	protein	71	Bos taurus	P63212 (AlphaFold model)

Sequence of entity 1 (P), FASTA

>21LT_1 Setmelanotide (chains P)
RCAHFRWC

Sequence of entity 2 (R), FASTA

>21LT_2 Melanocortin receptor 4,LgBiT subunit (chains R)
MVNSTHRGMHTSLHLWNRSSYRLHSNASESLGKGYSDGGCYEQLFVSPEVFVTLGVISLL
ENILVIVAIAKNKNLHSPMYFFICSLAVADMLVSVSNGSETIVITLLNSTDTDAQSFTVN
IDNVIDSVICSSLLASICSLLSIAVDRYFTIFYALQYHNIMTVKRVGIIISCIWAACTVS
GILFIIYSDSSAVIICLITMFFTMLALMASLYVHMFLMARLHIKRIAVLPGTGAIRQGAN
MKGAITLTILIGVFVVCWAPFFLHLIFYISCPQNPYCVCFMSHFNLYLILIMCNSIIDPL
IYALRSQELRKTFKEIICCYPLGGLCDLSSRYGSSGGGGSGGGGSSGVFTLEDFVGDWEQ
TAAYNLDQVLEQGGVSSLLQNLAVSVTPIQRIVRSGENALKIDIHVIIPYEGLSADQMAQ
IEEVFKVVYPVDDHHFKVILPYGTLVIDGVTPNMLNYFGRPYEGIAVFDGKKITVTGTLW
NGNKIIDERLITPDGSMLFRVTINS

Sequence of entity 3 (A), FASTA

>21LT_3 G subunit q (Gi1-Gq chimeric) (chains A)
MGCTLSAEDKAAVERSKMIEKQLQKDKQVYRRTLRLLLLGADNSGKSTIVKQMRIYHVNG
YSEEECKQYKAVVYSNTIQSIIAIIRAMGRLKIDFGDSARADDARQLFVLAGAAEEGFMT
AELAGVIKRLWKDSGVQACFNRSREYQLNDSAAYYLNDLDRIAQPNYIPTQQDVLRTRVK
TSGIFETKFQVDKVNFHMFDVGAQRDERRKWIQCFNDVTAIIFVVDSSDYNRLQEALNDF
KSIWNNRWLRTISVILFLNKQDLLAEKVLAGKSKIEDYFPEFARYTTPEDATPEPGEDPR
VTRAKYFIRKEFVDISTASGDGRHICYPHFTCSVDTENARRIFNDCKDIILQMNLREYNL
V

Sequence of entity 4 (B), FASTA

>21LT_4 Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1,HiBiT (chains B)
MGSLLQSELDQLRQEAEQLKNQIRDARKACADATLSQITNNIDPVGRIQMRTRRTLRGHL
AKIYAMHWGTDSRLLVSASQDGKLIIWDSYTTNKVHAIPLRSSWVMTCAYAPSGNYVACG
GLDNICSIYNLKTREGNVRVSRELAGHTGYLSCCRFLDDNQIVTSSGDTTCALWDIETGQ
QTTTFTGHTGDVMSLSLAPDTRLFVSGACDASAKLWDVREGMCRQTFTGHESDINAICFF
PNGNAFATGSDDATCRLFDLRADQELMTYSHDNIICGITSVSFSKSGRLLLAGYDDFNCN
VWDALKADRAGVLAGHDNRVSCLGVTDDGMAVATGSWDSFLKIWNGSSGGGGSGGGGSSG
VSGWRLFKKIS

Sequence of entity 5 (G), FASTA

>21LT_5 Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 (chains G)
MASNNTASIAQARKLVEQLKMEANIDRIKVSKAAADLMAYCEAHAKEDPLLTPVPASENP
FREKKFFCAIL

Ligands and cofactors

ID	Name	Formula	Copies
CA	Calcium ion	Ca	1

Primary citation

Rationale of renewed efforts in developing MC4R modulators to treat metabolic disorders. Feng, W., Zhou, Q., Wang, M.W. Acta Pharm Sin B (2026) 16:5016-5033. DOI 10.1016/j.apsb.2026.06.035 · 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
7PIV 2.86 Å, Active Melanocortin-4 receptor (MC4R)- Gs protein complex bound to agonist NDP-alpha-MSH…
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
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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