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- EMDB-36593: Small molecule agonist (PCO371) bound to human parathyroid hormon... -

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Entry
Database: EMDB / ID: EMD-36593
TitleSmall molecule agonist (PCO371) bound to human parathyroid hormone receptor type 1 (PTH1R)
Map data
Sample
  • Complex: A conserved and druggable pocket in class B G protein coupled receptors for 2 orally active small molecule agonists
    • Protein or peptide: Guanine nucleotide-binding protein G(s) subunit alpha-1
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
    • Protein or peptide: Nanobody 35
    • Protein or peptide: Parathyroid hormone/parathyroid hormone-related peptide receptor
  • Ligand: PCO-371
KeywordsClass B / GPCR / MEMBRANE PROTEIN
Function / homology
Function and homology information


parathyroid hormone receptor activity / Class B/2 (Secretin family receptors) / G protein-coupled peptide receptor activity / osteoblast development / positive regulation of inositol phosphate biosynthetic process / bone mineralization / peptide hormone binding / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / chondrocyte differentiation / bone resorption ...parathyroid hormone receptor activity / Class B/2 (Secretin family receptors) / G protein-coupled peptide receptor activity / osteoblast development / positive regulation of inositol phosphate biosynthetic process / bone mineralization / peptide hormone binding / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / chondrocyte differentiation / bone resorption / cell maturation / skeletal system development / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / Olfactory Signaling Pathway / Activation of the phototransduction cascade / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / G protein-coupled acetylcholine receptor signaling pathway / adenylate cyclase-activating G protein-coupled receptor signaling pathway / G-protein activation / intracellular calcium ion homeostasis / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through CDC42 / Glucagon signaling in metabolic regulation / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / ADP signalling through P2Y purinoceptor 12 / Sensory perception of sweet, bitter, and umami (glutamate) taste / photoreceptor disc membrane / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / G alpha (z) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / cellular response to catecholamine stimulus / ADORA2B mediated anti-inflammatory cytokines production / ADP signalling through P2Y purinoceptor 1 / G beta:gamma signalling through PI3Kgamma / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / adenylate cyclase-activating dopamine receptor signaling pathway / GPER1 signaling / Inactivation, recovery and regulation of the phototransduction cascade / cellular response to prostaglandin E stimulus / G-protein beta-subunit binding / heterotrimeric G-protein complex / G alpha (12/13) signalling events / sensory perception of taste / extracellular vesicle / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / GTPase binding / Ca2+ pathway / retina development in camera-type eye / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / fibroblast proliferation / G alpha (i) signalling events / basolateral plasma membrane / G alpha (s) signalling events / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (q) signalling events / in utero embryonic development / Ras protein signal transduction / Extra-nuclear estrogen signaling / cell population proliferation / receptor complex / cell surface receptor signaling pathway / G protein-coupled receptor signaling pathway / apical plasma membrane / lysosomal membrane / negative regulation of cell population proliferation / GTPase activity / positive regulation of cell population proliferation / synapse / protein-containing complex binding / nucleolus / signal transduction / protein homodimerization activity / extracellular exosome / nucleus / membrane / plasma membrane / cytosol / cytoplasm
Similarity search - Function
GPCR, family 2, parathyroid hormone receptor / G-protein coupled receptors family 2 signature 1. / : / GPCR, family 2, extracellular hormone receptor domain / G-protein coupled receptors family 2 profile 1. / Domain present in hormone receptors / Hormone receptor domain / GPCR family 2, extracellular hormone receptor domain superfamily / G-protein coupled receptors family 2 signature 2. / GPCR, family 2, secretin-like, conserved site ...GPCR, family 2, parathyroid hormone receptor / G-protein coupled receptors family 2 signature 1. / : / GPCR, family 2, extracellular hormone receptor domain / G-protein coupled receptors family 2 profile 1. / Domain present in hormone receptors / Hormone receptor domain / GPCR family 2, extracellular hormone receptor domain superfamily / G-protein coupled receptors family 2 signature 2. / GPCR, family 2, secretin-like, conserved site / GPCR, family 2, secretin-like / 7 transmembrane receptor (Secretin family) / GPCR, family 2-like / G-protein coupled receptors family 2 profile 2. / G-protein, gamma subunit / G-protein gamma subunit domain profile. / G-protein gamma-like domain / G-protein gamma-like domain superfamily / GGL domain / G protein gamma subunit-like motifs / GGL domain / Guanine nucleotide-binding protein, beta subunit / G-protein, beta subunit / G-protein beta WD-40 repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / WD domain, G-beta repeat / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily
Similarity search - Domain/homology
Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Parathyroid hormone/parathyroid hormone-related peptide receptor
Similarity search - Component
Biological speciesHomo sapiens (human) / Mus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.57 Å
AuthorsZhao L / He Q / Yuan Q / Gu Y / He X / Shan H / Li J / Wang K / Li Y / Hu W ...Zhao L / He Q / Yuan Q / Gu Y / He X / Shan H / Li J / Wang K / Li Y / Hu W / Wu K / Shen J / Xu HE
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: Nature / Year: 2023
Title: Conserved class B GPCR activation by a biased intracellular agonist.
Authors: Li-Hua Zhao / Qian He / Qingning Yuan / Yimin Gu / Xinheng He / Hong Shan / Junrui Li / Kai Wang / Yang Li / Wen Hu / Kai Wu / Jianhua Shen / H Eric Xu /
Abstract: Class B G-protein-coupled receptors (GPCRs), including glucagon-like peptide 1 receptor (GLP1R) and parathyroid hormone 1 receptor (PTH1R), are important drug targets. Injectable peptide drugs ...Class B G-protein-coupled receptors (GPCRs), including glucagon-like peptide 1 receptor (GLP1R) and parathyroid hormone 1 receptor (PTH1R), are important drug targets. Injectable peptide drugs targeting these receptors have been developed, but orally available small-molecule drugs remain under development. Here we report the high-resolution structure of human PTH1R in complex with the stimulatory G protein (G) and a small-molecule agonist, PCO371, which reveals an unexpected binding mode of PCO371 at the cytoplasmic interface of PTH1R with G. The PCO371-binding site is totally different from all binding sites previously reported for small molecules or peptide ligands in GPCRs. The residues that make up the PCO371-binding pocket are conserved in class B GPCRs, and a single alteration in PTH2R and two residue alterations in GLP1R convert these receptors to respond to PCO371. Functional assays reveal that PCO371 is a G-protein-biased agonist that is defective in promoting PTH1R-mediated arrestin signalling. Together, these results uncover a distinct binding site for designing small-molecule agonists for PTH1R and possibly other members of the class B GPCRs and define a receptor conformation that is specific only for G-protein activation but not arrestin signalling. These insights should facilitate the design of distinct types of class B GPCR small-molecule agonist for various therapeutic indications.
History
DepositionJun 16, 2023-
Header (metadata) releaseAug 2, 2023-
Map releaseAug 2, 2023-
UpdateNov 6, 2024-
Current statusNov 6, 2024Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_36593.png

Downloads & links

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Map

FileDownload / File: emd_36593.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.82 Å/pix.
x 256 pix.
= 210.944 Å		0.82 Å/pix.
x 256 pix.
= 210.944 Å		0.82 Å/pix.
x 256 pix.
= 210.944 Å

Surface

Projections

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.824 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.013
Minimum - Maximum-0.056274842 - 0.090764426
Average (Standard dev.)0.00006222027 (±0.0020516822)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 210.944 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_36593_half_map_1.map
Projections & Slices
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Half map: #2

Fileemd_36593_half_map_2.map
Projections & Slices
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Sample components

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Entire : A conserved and druggable pocket in class B G protein coupled rec...

EntireName: A conserved and druggable pocket in class B G protein coupled receptors for 2 orally active small molecule agonists
Components
  • Complex: A conserved and druggable pocket in class B G protein coupled receptors for 2 orally active small molecule agonists
    • Protein or peptide: Guanine nucleotide-binding protein G(s) subunit alpha-1
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
    • Protein or peptide: Nanobody 35
    • Protein or peptide: Parathyroid hormone/parathyroid hormone-related peptide receptor
  • Ligand: PCO-371

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Supramolecule #1: A conserved and druggable pocket in class B G protein coupled rec...

SupramoleculeName: A conserved and druggable pocket in class B G protein coupled receptors for 2 orally active small molecule agonists
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#5
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 160 KDa

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Macromolecule #1: Guanine nucleotide-binding protein G(s) subunit alpha-1

MacromoleculeName: Guanine nucleotide-binding protein G(s) subunit alpha-1
type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 41.879465 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MGCTLSAEDK AAVERSKMIE KQLQKDKQVY RATHRLLLLG ADNSGKSTIV KQMRIYHVNG YSEEECKQYK AVVYSNTIQS IIAIIRAMG RLKIDFGDSA RADDARQLFV LAGAAEEGFM TAELAGVIKR LWKDSGVQAC FNRSREYQLN DSAAYYLNDL D RIAQPNYI ...String:
MGCTLSAEDK AAVERSKMIE KQLQKDKQVY RATHRLLLLG ADNSGKSTIV KQMRIYHVNG YSEEECKQYK AVVYSNTIQS IIAIIRAMG RLKIDFGDSA RADDARQLFV LAGAAEEGFM TAELAGVIKR LWKDSGVQAC FNRSREYQLN DSAAYYLNDL D RIAQPNYI PTQQDVLRTR VKTSGIFETK FQVDKVNFHM FDVGAQRDER RKWIQCFNDV TAIIFVVDSS DYNRLQEALN DF KSIWNNR WLRTISVILF LNKQDLLAEK VLAGKSKIED YFPEFARYTT PEDATPEPGE DPRVTRAKYF IRDEFLRIST ASG DGRHYC YPHFTCSVDT ENARRIFNDC RDIIQRMHLR QYELL

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Macromolecule #2: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1

MacromoleculeName: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 38.330793 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: GSLLQSELDQ LRQEAEQLKN QIRDARKACA DATLSQITNN IDPVGRIQMR TRRTLRGHLA KIYAMHWGTD SRLLVSASQD GKLIIWDSY TTNKVHAIPL RSSWVMTCAY APSGNYVACG GLDNICSIYN LKTREGNVRV SRELAGHTGY LSCCRFLDDN Q IVTSSGDT ...String:
GSLLQSELDQ LRQEAEQLKN QIRDARKACA DATLSQITNN IDPVGRIQMR TRRTLRGHLA KIYAMHWGTD SRLLVSASQD GKLIIWDSY TTNKVHAIPL RSSWVMTCAY APSGNYVACG GLDNICSIYN LKTREGNVRV SRELAGHTGY LSCCRFLDDN Q IVTSSGDT TCALWDIETG QQTTTFTGHT GDVMSLSLAP DTRLFVSGAC DASAKLWDVR EGMCRQTFTG HESDINAICF FP NGNAFAT GSDDATCRLF DLRADQELMT YSHDNIICGI TSVSFSKSGR LLLAGYDDFN CNVWDALKAD RAGVLAGHDN RVS CLGVTD DGMAVATGSW DSFLKIWNGS SGGGGS

UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1

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Macromolecule #3: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2

MacromoleculeName: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 7.861143 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString:
MASNNTASIA QARKLVEQLK MEANIDRIKV SKAAADLMAY CEAHAKEDPL LTPVPASENP FREKKFFCAI L

UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2

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Macromolecule #4: Nanobody 35

MacromoleculeName: Nanobody 35 / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 15.343019 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
MAQVQLQESG GGLVQPGGSL RLSCAASGFT FSNYKMNWVR QAPGKGLEWV SDISQSGASI SYTGSVKGRF TISRDNAKNT LYLQMNSLK PEDTAVYYCA RCPAPFTRDC FDVTSTTYAY RGQGTQVTVS SHHHHHHEPE A

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Macromolecule #5: Parathyroid hormone/parathyroid hormone-related peptide receptor

MacromoleculeName: Parathyroid hormone/parathyroid hormone-related peptide receptor
type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 54.78302 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: DADDVMTKEE QIFLLHRAQA QCEKRLKEVL QRPASIMESD KGWTSASTSG KPRKDKASGK LYPESEEDKE APTGSRYRGR PCLPEWDHI LCWPLGAPGE VVAVPCPDYI YDFNHKGHAY RRCDRNGSWE LVPGHNRTWA NYSECVKFLT NETREREVFD R LAMIYTVG ...String:
DADDVMTKEE QIFLLHRAQA QCEKRLKEVL QRPASIMESD KGWTSASTSG KPRKDKASGK LYPESEEDKE APTGSRYRGR PCLPEWDHI LCWPLGAPGE VVAVPCPDYI YDFNHKGHAY RRCDRNGSWE LVPGHNRTWA NYSECVKFLT NETREREVFD R LAMIYTVG YSVSLASLTV AVLILAYFRR LHCTRNYIHM HLFLSFMLRA VSIFVKDAVL YSGATLDEAE RLTEEELRAI AQ APPPPAT AAAGYAGCRV AVTFFLYFLA TNYYWILVEG LYLHSLIFMA FFSEKKYLWG FTVFGWGLPA VFVAVWVSVR ATL ANTGCW DLSSGNKKWI IQVPILASIV LNFILFINIV RVLATKLRET NAGRCDTRQQ YRKLLKSTLV LMPLFGVHYI VFMA TPYTE VSGTLWQVQM HYEMLFNSFQ GFFVAIIYCF CNGEVQAEIK KSWSRWTLAL DFRRKARSGS SSYSYGPMVS HEF

UniProtKB: Parathyroid hormone/parathyroid hormone-related peptide receptor

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Macromolecule #6: PCO-371

MacromoleculeName: PCO-371 / type: ligand / ID: 6 / Number of copies: 1 / Formula: KHF
Molecular weightTheoretical: 635.654 Da
Chemical component information

ChemComp-KHF:
PCO-371

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.04
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 18.0 µm / Nominal defocus min: 8.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.57 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 1099315
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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