7PIU: Agonist setmelanotide
Cryo-EM structure of the agonist setmelanotide bound to the active melanocortin-4 receptor (MC4R) in complex with the heterotrimeric Gs protein at 2.6 A resolution. Determined by electron microscopy at 2.58 Å resolution. Released 17 Nov 2021.
- Method
- Electron microscopy
- Resolution
- 2.58 Å
- Organisms
- Homo sapiens, synthetic construct, Rattus norvegicus
- Chains
- 6
- Atoms
- 7,788
- Mol. weight
- 144.45 kDa
- Ligands
- CA
- Released
- 17 Nov 2021
Explore 7PIU in 3D
Show helices and sheets
RCSB PDB
PDBe
Secondary structure: helices and β-sheets
7PIU contains 29 α-helices and 45 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: 6 helices, 6 β-strands
| Element | Residues | Length | Sheet |
|---|
| α-helix | 15-39 | 25 | |
| β-strand | 41-46 | 6 | 1 |
| β-strand | 194-199 | 6 | 1 |
| β-strand | 204-209 | 6 | 1 |
| α-helix | 220-224 | 5 | |
| β-strand | 229-235 | 7 | 1 |
| α-helix | 251-263 | 13 | |
| β-strand | 272-278 | 7 | 1 |
| α-helix | 299-303 | 5 | |
| α-helix | 319-338 | 20 | |
| β-strand | 345-349 | 5 | 1 |
| α-helix | 357-376 | 20 | |
Chain B: 5 helices, 28 β-strands
| Element | Residues | Length | Sheet |
|---|
| α-helix | 5-24 | 20 | |
| α-helix | 30-33 | 4 | |
| α-helix | 38-39 | 2 | |
| 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 |
| 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 | 166-170 | 5 | 5 |
| β-strand | 175-180 | 6 | 5 |
| α-helix | 186 | 1 | |
| β-strand | 187-192 | 6 | 6 |
| β-strand | 198-203 | 6 | 6 |
| β-strand | 207-212 | 6 | 6 |
| β-strand | 217-223 | 7 | 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 |
| α-helix | 272 | 1 | |
| β-strand | 273-278 | 6 | 8 |
| β-strand | 284-289 | 6 | 8 |
| β-strand | 294-298 | 5 | 8 |
| β-strand | 304-308 | 5 | 8 |
| 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 | Sheet |
|---|
| α-helix | 10-23 | 14 | |
| α-helix | 30-43 | 14 | |
| α-helix | 53-55 | 3 | |
Chain N: 2 helices, 11 β-strands
| Element | Residues | Length | Sheet |
|---|
| β-strand | 3-7 | 5 | 9 |
| β-strand | 10-12 | 3 | 10 |
| β-strand | 18-25 | 8 | 9 |
| α-helix | 29-31 | 3 | |
| β-strand | 34-39 | 6 | 10 |
| β-strand | 46-51 | 6 | 10 |
| β-strand | 58-60 | 3 | 10 |
| β-strand | 68-73 | 6 | 9 |
| β-strand | 78-83 | 6 | 9 |
| α-helix | 88-90 | 3 | |
| β-strand | 92-98 | 7 | 10 |
| β-strand | 118 | 1 | 10 |
| β-strand | 122-126 | 5 | 10 |
Chain R: 13 helices, 0 β-strands
| Element | Residues | Length | Sheet |
|---|
| α-helix | 44-47 | 4 | |
| α-helix | 48-70 | 23 | |
| α-helix | 73-75 | 3 | |
| α-helix | 78-106 | 29 | |
| α-helix | 118-152 | 35 | |
| α-helix | 157-160 | 4 | |
| α-helix | 163-186 | 24 | |
| α-helix | 192-226 | 35 | |
| α-helix | 241-270 | 30 | |
| α-helix | 275-281 | 7 | |
| α-helix | 284-301 | 18 | |
| α-helix | 303-305 | 3 | |
| 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) |
| Setmelanotide (other names RM-493; BIM-22493; IRC-022493; Imcivree) | P | protein | 8 | synthetic construct | |
| 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 | Bos taurus | P63212 (AlphaFold model) |
| Camelid antibody fragment - nanobody 35 | N | protein | 134 | Lama glama | |
Sequence of entity 1 (R), FASTA
>7PIU_1 Melanocortin receptor 4 (chains R)
DYKDDDDKMVNSTHRGMHTSLHLWNRSSYRLHSNASESLGKGYSDGGCYEQLFVSPEVFV
TLGVISLLENILVIVAIAKNKNLHSPMYFFICSLAVADMLVSVSNGSETIVITLLNSTDT
DAQSFTVNIDNVIDSVICSSLLASICSLLSIAVDRYFTIFYALQYHNIMTVKRVGIIISC
IWAACTVSGILFIIYSDSSAVIICLITMFFTMLALMASLYVHMFLMARLHIKRIAVLPGT
GAIRQGANMKGAITLTILIGVFVVCWAPFFLHLIFYISCPQNPYCVCFMSHFNLYLILIM
CNSIIDPLIYALRSQELRKTFKEIICCYPLGGLCDLSSRYLEVLFQ
Sequence of entity 2 (P), FASTA
>7PIU_2 Setmelanotide (other names RM-493; BIM-22493; IRC-022493; Imcivree) (chains P)
RCAHFRWC
Sequence of entity 3 (A), FASTA
>7PIU_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
>7PIU_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
>7PIU_5 Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 (chains G)
MASNNTASIAQARKLVEQLKMEANIDRIKVSKAAADLMAYCEAHAKEDPLLTPVPASENP
FREKKFFCAIL
Sequence of entity 6 (N), FASTA
>7PIU_6 Camelid antibody 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:
- 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
- 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
Browse structure collections
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