9B65: Biased agonist bound CB1-Gi structure

Biased agonist bound CB1-Gi structure. Determined by electron microscopy at 3.03 Å resolution. Released 5 Mar 2025.

Method: Electron microscopy
Resolution: 3.03 Å
Organisms: Homo sapiens, Mus musculus
Chains: 5
Atoms: 8,463
Mol. weight: 169.81 kDa
Ligands: KCA
Released: 5 Mar 2025

Explore 9B65 in 3D Show helices and sheets RCSB PDB PDBe

Secondary structure: helices and β-sheets

9B65 contains 39 α-helices and 64 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: 9 helices, 11 β-strands

Element	Residues	Length	Sheet
α-helix	7-28	22
β-strand	33-39	7	1
α-helix	46-49	4
β-strand	185	1	1
β-strand	188-190	3	1
β-strand	195-200	6	1
α-helix	208-211	4
α-helix	212-215	4
β-strand	220-223	4	1
β-strand	224-226	3	2
α-helix	227-229	3
α-helix	243-253	11
β-strand	263	1	1
β-strand	264	1	3
β-strand	267-269	3	2
α-helix	273-280	8
α-helix	297-310	14
β-strand	319	1	3
β-strand	322-323	2	2
α-helix	330-350	21

Chain B: 4 helices, 29 β-strands

Element	Residues	Length	Sheet
α-helix	4-7	4
α-helix	11-24	14
α-helix	30-33	4
β-strand	43	1	4
β-strand	47-52	6	5
β-strand	58-63	6	6
β-strand	69-74	6	6
β-strand	78-83	6	6
β-strand	89-94	6	6
β-strand	100-105	6	7
β-strand	111-116	6	7
β-strand	120-125	6	7
β-strand	134-140	7	7
β-strand	146-153	8	8
β-strand	156-161	6	8
β-strand	165-170	6	8
β-strand	178-180	3	8
β-strand	187-192	6	9
β-strand	198-203	6	9
β-strand	207-212	6	9
β-strand	218-223	6	9
β-strand	229-234	6	10
β-strand	240-245	6	10
β-strand	250-254	5	10
β-strand	259-264	6	10
β-strand	273-278	6	11
α-helix	279	1
β-strand	284-289	6	11
β-strand	294-298	5	11
β-strand	304-307	4	11
β-strand	317-320	4	5
β-strand	327-330	4	5
β-strand	335-339	5	5

Chain C: 3 helices, 0 β-strands

Element	Residues	Length
α-helix	9-21	13
α-helix	30-41	12
α-helix	54-55	2

Chain R: 16 helices, 0 β-strands

Element	Residues	Length
α-helix	113-115	3
α-helix	116-120	5
α-helix	122-126	5
α-helix	134-137	4
α-helix	138-141	4
α-helix	155-171	17
α-helix	173-176	4
α-helix	190-219	30
α-helix	235-246	12
α-helix	276-286	11
α-helix	291-310	20
α-helix	342-356	15
α-helix	358-365	8
α-helix	379-382	4
α-helix	385-394	10
α-helix	395-399	5

Chain S: 7 helices, 24 β-strands

Element	Residues	Length	Sheet
β-strand	3-7	5	12
β-strand	11-12	2	13
β-strand	19-25	7	12
α-helix	29-31	3
β-strand	33-39	7	14
β-strand	45-51	7	14
α-helix	53-55	3
β-strand	58-60	3	14
α-helix	62-64	3
β-strand	68-73	6	12
β-strand	78-83	6	12
α-helix	88-90	3
β-strand	92-99	8	14
β-strand	110-111	2	14
β-strand	115-117	3	14
β-strand	118-119	2	13
β-strand	128-129	2	15
β-strand	143-149	7	15
β-strand	154	1	16
β-strand	160	1	16
β-strand	162-167	6	17
β-strand	174-178	5	17
β-strand	182-183	2	17
α-helix	184	1
β-strand	191-195	5	15
β-strand	199-204	6	15
β-strand	213-219	7	17
α-helix	225	1
β-strand	226-227	2	17
α-helix	228-230	3
β-strand	232-233	2	17

Molecules and chains

Molecule	Chains	Type	Length	Organism	UniProt
Guanine nucleotide-binding protein G(i) subunit alpha-1	A	protein	354	Homo sapiens	P63096 (AlphaFold model)
Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1	B	protein	344	Homo sapiens	P62873 (AlphaFold model)
Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2	C	protein	71	Homo sapiens	P59768 (AlphaFold model)
Cannabinoid receptor 1	R	protein	495	Homo sapiens	P21554 (AlphaFold model)
scFv16	S	protein	259	Mus musculus

Sequence of entity 1 (A), FASTA

>9B65_1 Guanine nucleotide-binding protein G(i) subunit alpha-1 (chains A)
MGCTLSAEDKAAVERSKMIDRNLREDGEKAAREVKLLLLGAGESGKSTIVKQMKIIHEAG
YSEEECKQYKAVVYSNTIQSIIAIIRAMGRLKIDFGDSARADDARQLFVLAGAAEEGFMT
AELAGVIKRLWKDSGVQACFNRSREYQLNDSAAYYLNDLDRIAQPNYIPTQQDVLRTRVK
TTGIVETHFTFKDLHFKMFDVGGQRSERKKWIHCFEGVTAIIFCVALSDYDLVLAEDEEM
NRMHESMKLFDSICNNKWFTDTSIILFLNKKDLFEEKIKKSPLTICYPEYAGSNTYEEAA
AYIQCQFEDLNKRKDTKEIYTHFTCATDTKNVQFVFDAVTDVIIKNNLKDCGLF

Sequence of entity 2 (B), FASTA

>9B65_2 Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 (chains B)
PGSSGSELDQLRQEAEQLKNQIRDARKACADATLSQITNNIDPVGRIQMRTRRTLRGHLA
KIYAMHWGTDSRLLVSASQDGKLIIWDSYTTNKVHAIPLRSSWVMTCAYAPSGNYVACGG
LDNICSIYNLKTREGNVRVSRELAGHTGYLSCCRFLDDNQIVTSSGDTTCALWDIETGQQ
TTTFTGHTGDVMSLSLAPDTRLFVSGACDASAKLWDVREGMCRQTFTGHESDINAICFFP
NGNAFATGSDDATCRLFDLRADQELMTYSHDNIICGITSVSFSKSGRLLLAGYDDFNCNV
WDALKADRAGVLAGHDNRVSCLGVTDDGMAVATGSWDSFLKIWN

Sequence of entity 3 (C), FASTA

>9B65_3 Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 (chains C)
MASNNTASIAQARKLVEQLKMEANIDRIKVSKAAADLMAYCEAHAKEDPLLTPVPASENP
FREKKFFCAIL

Sequence of entity 4 (R), FASTA

>9B65_4 Cannabinoid receptor 1 (chains R)
DYKDDDDAMKSILDGLADTTFRTITTDLLYVGSNDIQYEDIKGDMASKLGYFPQKFPLTS
FRGSPFQEKMTAGDNPQLVPADQVNITEFYNKSLSENLYFQGSFKENEENIQCGENFMDI
ECFMVLNPSQQLAIAVLSLTLGTFTVLENLLVLCVILHSRSLRCRPSYHFIGSLAVADLL
GSVIFVYSFIDFHVFHRKDSRNVFLFKLGGVTASFTASVGSLFLTAIDRYISIHRPLAYK
RIVTRPKAVVAFCLMWTIAIVIAVLPLLGWNCEKLQSVCSDIFPHIDETYLMFWIGVTSV
LLLFIVYAYMYILWKAHSHAVRMIQRGTQKSIIIHTSEDGKVQVTRPDQARMDIRLAKTL
VLILVVLIICWGPLLAIMVYDVFGKMNKLIKTVFAFCSMLCLLNSTVNPIIYALRSKDLR
HAFRSMFPSCEGTAQPLDNSMGDSDCLHKHANNAASVHRAAESCIKSTVKIAKVTMSVST
DTSAEALGSHHHHHH

Sequence of entity 5 (S), FASTA

>9B65_5 scFv16 (chains S)
DVQLVESGGGLVQPGGSRKLSCSASGFAFSSFGMHWVRQAPEKGLEWVAYISSGSGTIYY
ADTVKGRFTISRDDPKNTLFLQMTSLRSEDTAMYYCVRSIYYYGSSPFDFWGQGTTLTVS
SGGGGSGGGGSGGGGSDIVMTQATSSVPVTPGESVSISCRSSKSLLHSNGNTYLYWFLQR
PGQSPQLLIYRMSNLASGVPDRFSGSGSGTAFTLTISRLEAEDVGVYYCMQHLEYPLTFG
AGTKLELKAAAHHHHHHHH

Ligands and cofactors

ID	Name	Formula	Copies
KCA	methyl N-{1-[(4-fluorophenyl)methyl]-1H-indazole-3-carbonyl}-3-methyl-L-valinate	C22 H24 F N3 O3	1

Primary citation

A cryptic pocket in CB1 drives peripheral and functional selectivity. Rangari, V.A., O'Brien, E.S., Powers, A.S. et al. Nature (2025) 640:265-273. DOI 10.1038/s41586-025-08618-7 · PubMed

Other PDB entries of the same protein (UniProt P63096 (AlphaFold model), which also has an AlphaFold model), best resolution first:

6CRK 2.0 Å, Heterotrimeric G-protein in complex with an antibody fragment
3UMR 2.04 Å, Crystal structure of the G202D mutant of human G-alpha-i1
9P7Z 2.1 Å, NTSR1-Gi-NTS(8-13) Complex in the Canonical, AHD Open State (C-Open-Apo)
2OM2 2.2 Å, Crystal Structure Of Human G[alpha]i1 Bound To The Goloco Motif Of Rgs14
8YN9 2.3 Å, Cryo-EM structure of histamine H4 receptor in complex with histamine and Gi
9HYI 2.3 Å, DP81-bound serotonin 5-HT1A receptor - Gi Protein Complex
9O36 2.3 Å, CryoEM structure of mu-opioid receptor - Gi protein complex bound to fluornitrazene (FNZ)
9P80 2.3 Å, NTSR1-Gi-NTS(8-13) Complex in the Non-Canonical, AHD Open State (NC-Open-Apo)
8XXV 2.33 Å, Cryo-EM Structure of the Prostaglandin D2 Receptor 2-indomethacin Coupled to G Protein
3UMS 2.34 Å, Crystal structure of the G202A mutant of human G-alpha-i1
3ONW 2.38 Å, Structure of a G-alpha-i1 mutant with enhanced affinity for the RGS14 GoLoco motif.
20ZG 2.4 Å, Cryo-EM structure of the human neurotensin receptor 1 (hNTSR1)-Gi1 complex in the…

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