7TRP: Muscarinic acetylcholine receptor M4

Human M4 muscarinic acetylcholine receptor complex with Gi1 and the agonist iperoxo and positive allosteric modulator LY2033298. Determined by electron microscopy at 2.4 Å resolution. Released 17 May 2023.

Method: Electron microscopy
Resolution: 2.4 Å
Organisms: Homo sapiens, Mus musculus
Chains: 5
Atoms: 8,681
Mol. weight: 153.12 kDa
Ligands: IXO, IUE
Released: 17 May 2023

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

Secondary structure: helices and β-sheets

7TRP contains 41 α-helices and 60 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: 12 helices, 8 β-strands

Element	Residues	Length	Sheet
α-helix	7-31	25
β-strand	34-40	7	13
α-helix	46-54	9
β-strand	185-191	7	13
β-strand	194-200	7	13
α-helix	208-210	3
α-helix	212-215	4
β-strand	220-226	7	13
α-helix	227-230	4
α-helix	232	1
β-strand	233	1	14
α-helix	234	1
β-strand	241	1	14
α-helix	242-254	13
β-strand	263-269	7	13
α-helix	271-280	10
α-helix	283-285	3
α-helix	296-308	13
β-strand	319-322	4	13
α-helix	332-350	19

Chain B: 4 helices, 28 β-strands

Element	Residues	Length	Sheet
α-helix	3-24	22
α-helix	30-33	4
α-helix	38-39	2
β-strand	47-51	5	1
β-strand	58-63	6	2
β-strand	69-74	6	2
β-strand	78-83	6	2
β-strand	88-94	7	2
β-strand	100-105	6	3
β-strand	111-116	6	3
β-strand	120-125	6	3
β-strand	134-140	7	3
β-strand	146-151	6	4
β-strand	156-161	6	4
β-strand	165-170	6	4
β-strand	175-181	7	4
β-strand	187-192	6	5
β-strand	198-203	6	5
β-strand	207-212	6	5
β-strand	218-223	6	5
β-strand	229-234	6	6
β-strand	240-245	6	6
β-strand	250-254	5	6
β-strand	259-264	6	6
α-helix	272	1
β-strand	273-278	6	7
β-strand	284-289	6	7
β-strand	294-298	5	7
β-strand	304-308	5	7
β-strand	315-320	6	1
β-strand	327-331	5	1
β-strand	336-339	4	1

Chain G: 4 helices, 0 β-strands

Element	Residues	Length
α-helix	9-23	15
α-helix	30-43	14
α-helix	45-47	3
α-helix	53-55	3

Chain H: 5 helices, 24 β-strands

Element	Residues	Length	Sheet
β-strand	3-7	5	8
β-strand	10-12	3	9
β-strand	17-25	9	8
α-helix	29-31	3
β-strand	33-39	7	9
β-strand	45-51	7	9
α-helix	53-55	3
β-strand	58-60	3	9
β-strand	68-73	6	8
β-strand	78-84	7	8
β-strand	92-99	8	9
β-strand	110-111	2	9
β-strand	115-119	5	9
β-strand	140-141	2	10
β-strand	146-148	3	11
β-strand	155-161	7	10
β-strand	166	1	12
β-strand	172	1	12
β-strand	174-179	6	11
β-strand	185-190	6	11
β-strand	194-195	2	11
α-helix	196	1
β-strand	203-207	5	10
β-strand	211-216	6	10
α-helix	221-223	3
β-strand	225-231	7	11
α-helix	237	1
β-strand	239	1	11
β-strand	243-246	4	11

Chain R: 16 helices, 0 β-strands

Element	Residues	Length
α-helix	34-59	26
α-helix	61-63	3
α-helix	67-80	14
α-helix	81-85	5
α-helix	86-95	10
α-helix	103-135	33
α-helix	146-174	29
α-helix	188-191	4
α-helix	193-200	8
α-helix	201-205	5
α-helix	206-222	17
α-helix	393-425	33
α-helix	432-447	16
α-helix	449	1
α-helix	450-454	5
α-helix	458-462	5

Molecules and chains

Molecule	Chains	Type	Length	Organism	UniProt
Muscarinic acetylcholine receptor M4	R	protein	349	Homo sapiens	P08173 (AlphaFold model)
Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1	B	protein	349	Homo sapiens	P62873 (AlphaFold model)
Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2	G	protein	70	Homo sapiens	P59768 (AlphaFold model)
Antibody fragment scFv16	H	protein	248	Mus musculus
Guanine nucleotide-binding protein G(i) subunit alpha-1	A	protein	354	Homo sapiens	P63096 (AlphaFold model)

Sequence of entity 1 (R), FASTA

>7TRP_1 Muscarinic acetylcholine receptor M4 (chains R)
DYKDDDDAMANFTPVNGSSGNQSVRLVTSSSHNRYETVEMVFIATVTGSLSLVTVVGNIL
VMLSIKVNRQLQTVNNYFLFSLACADLIIGAFSMNLYTVYIIKGYWPLGAVVCDLWLALD
YVVSNASVMNLLIISFDRYFCVTKPLTYPARRTTKMAGLMIAAAWVLSFVLWAPAILFWQ
FVVGKRTVPDNQCFIQFLSNPAVTFGTAIAAFYLPVVIMTVLYIHISLASRSRVHKHRPE
GPKEKKAKTKRQMAARERKVTRTIFAILLAFILTWTPYNVMVLVNTFCQSCIPDTVWSIG
YWLCYVNSTINPACYALCNATFKKTFRHLLLCQYRNIGTARHHHHHHHH

Sequence of entity 2 (B), FASTA

>7TRP_2 Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 (chains B)
HHHHHHGSSGSELDQLRQEAEQLKNQIRDARKACADATLSQITNNIDPVGRIQMRTRRTL
RGHLAKIYAMHWGTDSRLLVSASQDGKLIIWDSYTTNKVHAIPLRSSWVMTCAYAPSGNY
VACGGLDNICSIYNLKTREGNVRVSRELAGHTGYLSCCRFLDDNQIVTSSGDTTCALWDI
ETGQQTTTFTGHTGDVMSLSLAPDTRLFVSGACDASAKLWDVREGMCRQTFTGHESDINA
ICFFPNGNAFATGSDDATCRLFDLRADQELMTYSHDNIICGITSVSFSKSGRLLLAGYDD
FNCNVWDALKADRAGVLAGHDNRVSCLGVTDDGMAVATGSWDSFLKIWN

Sequence of entity 3 (G), FASTA

>7TRP_3 Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 (chains G)
ASNNTASIAQARKLVEQLKMEANIDRIKVSKAAADLMAYCEAHAKEDPLLTPVPASENPF
REKKFFCAIL

Sequence of entity 4 (H), FASTA

>7TRP_4 Antibody fragment scFv16 (chains H)
DVQLVESGGGLVQPGGSRKLSCSASGFAFSSFGMHWVRQAPEKGLEWVAYISSGSGTIYY
ADTVKGRFTISRDDPKNTLFLQMTSLRSEDTAMYYCVRSIYYYGSSPFDFWGQGTTLTVS
SGGGGSGGGGSGGGGSDIVMTQATSSVPVTPGESVSISCRSSKSLLHSNGNTYLYWFLQR
PGQSPQLLIYRMSNLASGVPDRFSGSGSGTAFTLTISRLEAEDVGVYYCMQHLEYPLTFG
AGTKLELK

Sequence of entity 5 (A), FASTA

>7TRP_5 Guanine nucleotide-binding protein G(i) subunit alpha-1 (chains A)
MGCTLSAEDKAAVERSKMIDRNLREDGEKAAREVKLLLLGAGESGKNTIVKQMKIIHEAG
YSEEECKQYKAVVYSNTIQSIIAIIRAMGRLKIDFGDSARADDARQLFVLAGAAEEGFMT
AELAGVIKRLWKDSGVQACFNRSREYQLNDSAAYYLNDLDRIAQPNYIPTQQDVLRTRVK
TTGIVETHFTFKDLHFKMFDVGAQRSERKKWIHCFEGVTAIIFCVALSDYDLVLAEDEEM
NRMHASMKLFDSICNNKWFTDTSIILFLNKKDLFEEKIKKSPLTICYPEYAGSNTYEEAA
AYIQCQFEDLNKRKDTKEIYTHFTCSTDTKNVQFVFDAVTDVIIKNNLKDCGLF

Ligands and cofactors

ID	Name	Formula	Copies
IXO	4-(4,5-dihydro-1,2-oxazol-3-yloxy)-N,N,N-trimethylbut-2-yn-1-aminium	C10 H17 N2 O2	1
IUE	3-amino-5-chloro-N-cyclopropyl-6-methoxy-4-methylthieno[2,3-b]pyridine-2-carbox…	C13 H14 Cl N3 O2 S	1

Primary citation

Structural and dynamic mechanisms of allostery at the M4 muscarinic acetylcholine receptor. Thal, D.M. Elife (2023).

Other PDB entries of the same protein (UniProt P08173 (AlphaFold model), which also has an AlphaFold model), best resolution first:

8FX5 2.45 Å, Human M4 muscarinic acetylcholine receptor complex with Gi1 and xanomeline
7TRQ 2.5 Å, Human M4 muscarinic acetylcholine receptor complex with Gi1 and the agonist iperoxo and…
9N09 2.57 Å, Human M4 muscarinic acetylcholine receptor Gi1 complex (mini-Gsi chimera) bound to the…
5DSG 2.6 Å, Structure of the M4 muscarinic acetylcholine receptor (M4-mT4L) bound to tiotropium
9N29 2.6 Å, hM4Di(GRANPA) in complex with mGsI and diphenhydramine
8E9X 2.7 Å, CryoEM structure of miniGo-coupled hM4Di in complex with DCZ
9KVP 2.79 Å, Structure of SB290157 bound to human C3aR in complex with Go (Full map)
7TRK 2.8 Å, Human M4 muscarinic acetylcholine receptor complex with Gi1 and the agonist iperoxo
7TRS 2.8 Å, Human M4 muscarinic acetylcholine receptor complex with Gi1 and the endogenous agonist…
9KVS 2.81 Å, Structure of SB290157 bound to human C3aR in complex with Go (Receptor Ligand Focused map)
9KV6 2.88 Å, Structure of mouse TLQP21 bound to mouse C3aR in complex with Go
6KP6 3.0 Å, The structural study of mutation induced inactivation of Human muscarinic receptor M4

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