PDB-6nbh: Cryo-EM structure of parathyroid hormone receptor type 1 in compl...

Basic information

• Entry: Database: PDB / ID: 6nbh
• Title: Cryo-EM structure of parathyroid hormone receptor type 1 in complex with a long-acting parathyroid hormone analog and G protein

Components

• (Guanine nucleotide-binding protein ...) x 2
• Gs protein alpha subunit
• Long-acting parathyroid hormone analog
• Nanobody-35
• Parathyroid hormone/parathyroid hormone-related peptide receptor

• Keywords: SIGNALING PROTEIN / Parathyroid hormone receptor / GPCR / Class B GPCR / GPCR-G protein complex

Function / homology

Function:

parathyroid hormone receptor activity / sensory perception of chemical stimulus / G-protein activation / Activation of the phototransduction cascade / Glucagon-type ligand receptors / Thromboxane signalling through TP receptor / Sensory perception of sweet, bitter, and umami (glutamate) taste / G beta:gamma signalling through PI3Kgamma / G beta:gamma signalling through CDC42 / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Ca2+ pathway / G protein-coupled peptide receptor activity / G alpha (z) signalling events / Vasopressin regulates renal water homeostasis via Aquaporins / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / Adrenaline,noradrenaline inhibits insulin secretion / ADP signalling through P2Y purinoceptor 12 / G alpha (q) signalling events / Class B/2 (Secretin family receptors) / G alpha (i) signalling events / Thrombin signalling through proteinase activated receptors (PARs) / Activation of G protein gated Potassium channels / G-protein activation / G beta:gamma signalling through PI3Kgamma / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through PLC beta / ADP signalling through P2Y purinoceptor 1 / Thromboxane signalling through TP receptor / Presynaptic function of Kainate receptors / G beta:gamma signalling through CDC42 / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / G alpha (12/13) signalling events / G beta:gamma signalling through BTK / alkylglycerophosphoethanolamine phosphodiesterase activity / ADP signalling through P2Y purinoceptor 12 / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / osteoblast development / Thrombin signalling through proteinase activated receptors (PARs) / Ca2+ pathway / G alpha (z) signalling events / Extra-nuclear estrogen signaling / G alpha (s) signalling events / G alpha (q) signalling events / positive regulation of inositol phosphate biosynthetic process / photoreceptor outer segment membrane / G alpha (i) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / spectrin binding / Vasopressin regulates renal water homeostasis via Aquaporins / bone mineralization / peptide hormone binding / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / mu-type opioid receptor binding / photoreceptor outer segment / corticotropin-releasing hormone receptor 1 binding / D1 dopamine receptor binding / chondrocyte differentiation / beta-2 adrenergic receptor binding / adenylate cyclase-activating adrenergic receptor signaling pathway / cell maturation / bone resorption / cardiac muscle cell apoptotic process / adenylate cyclase activator activity / photoreceptor inner segment / skeletal system development / ionotropic glutamate receptor binding / insulin-like growth factor receptor binding / G-protein beta/gamma-subunit complex binding / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / adenylate cyclase-activating G protein-coupled receptor signaling pathway / intracellular calcium ion homeostasis / cellular response to catecholamine stimulus / sensory perception of taste / adenylate cyclase-activating dopamine receptor signaling pathway / cellular response to prostaglandin E stimulus / G-protein beta-subunit binding / : / heterotrimeric G-protein complex / signaling receptor complex adaptor activity / GTPase binding / retina development in camera-type eye / phospholipase C-activating G protein-coupled receptor signaling pathway / positive regulation of cytosolic calcium ion concentration / cell body / cellular response to hypoxia / G alpha (s) signalling events / basolateral plasma membrane / in utero embryonic development / cell population proliferation / cell surface receptor signaling pathway / receptor complex / apical plasma membrane / G protein-coupled receptor signaling pathway / negative regulation of cell population proliferation / GTPase activity / dendrite

Domain/homology:

GPCR, family 2, parathyroid hormone receptor / Transducin (heterotrimeric G protein), gamma chain / G Protein Gi Gamma 2 / G-protein coupled receptors family 2 signature 1. / Hormone receptor domain / GPCR, family 2, extracellular hormone receptor domain / G-protein coupled receptors family 2 profile 1. / Domain present in hormone receptors / 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 alpha subunit, group S / YVTN repeat-like/Quinoprotein amine dehydrogenase / 7 Propeller / Methylamine Dehydrogenase; Chain H / G-alpha domain profile. / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G protein alpha subunit / G-protein, gamma subunit / G-protein gamma subunit domain profile. / GGL domain / G-protein gamma-like domain superfamily / G-protein gamma-like domain / GGL domain / G protein gamma subunit-like motifs / Guanine nucleotide-binding protein, beta subunit / G-protein, beta subunit / Few Secondary Structures / Irregular / G-protein beta WD-40 repeat / P-loop containing nucleotide triphosphate hydrolases / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD domain, G-beta repeat / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / P-loop containing nucleoside triphosphate hydrolase / Rossmann fold / 3-Layer(aba) Sandwich / Mainly Beta / Alpha Beta

Component:

CHOLESTEROL / PALMITIC ACID / Guanine nucleotide-binding protein G(s) subunit alpha isoforms short / Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / Parathyroid hormone/parathyroid hormone-related peptide receptor

• Biological species: Homo sapiens (human); Bos taurus (cattle); Rattus norvegicus (Norway rat); synthetic construct (others)
• Method: ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.5 Å
• Authors: Zhao, L.-H. / Ma, S. / Sutkeviciute, I. / Shen, D.-D. / Zhou, X.E. / de Waal, P.P. / Li, C.-Y. / Kang, Y. / Clark, L.J. / Jean-Alphonse, F.G. / White, A.D. / Xiao, K. / Yang, D. / Jiang, Y. / Watanabe, T. / Gardella, T.J. / Melcher, K. / Wang, M.-W. / Vilardaga, J.-P. / Xu, H.E. / Zhang, Y.

Funding support

China, United States, 5items

Organization	Grant number	Country
National Science Foundation (NSF, China)	Shanghai 18ZR1447800	China
National Natural Science Foundation of China (NSFC)	31300245	China
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)	GM127710	United States
National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease (NIH/NIDDK)	DK102495, DK111427, DK116780	United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)	008424	United States

• Citation: Journal: Science / Year: 2019; Title: Structure and dynamics of the active human parathyroid hormone receptor-1.; Authors: Li-Hua Zhao / Shanshan Ma / Ieva Sutkeviciute / Dan-Dan Shen / X Edward Zhou / Parker W de Waal / Chen-Yao Li / Yanyong Kang / Lisa J Clark / Frederic G Jean-Alphonse / Alex D White / Dehua Yang / Antao Dai / Xiaoqing Cai / Jian Chen / Cong Li / Yi Jiang / Tomoyuki Watanabe / Thomas J Gardella / Karsten Melcher / Ming-Wei Wang / Jean-Pierre Vilardaga / H Eric Xu / Yan Zhang / ; Abstract: The parathyroid hormone receptor-1 (PTH1R) is a class B G protein-coupled receptor central to calcium homeostasis and a therapeutic target for osteoporosis and hypoparathyroidism. Here we report the cryo-electron microscopy structure of human PTH1R bound to a long-acting PTH analog and the stimulatory G protein. The bound peptide adopts an extended helix with its amino terminus inserted deeply into the receptor transmembrane domain (TMD), which leads to partial unwinding of the carboxyl terminus of transmembrane helix 6 and induces a sharp kink at the middle of this helix to allow the receptor to couple with G protein. In contrast to a single TMD structure state, the extracellular domain adopts multiple conformations. These results provide insights into the structural basis and dynamics of PTH binding and receptor activation.

History

Deposition	Dec 7, 2018	Deposition site: RCSB / Processing site: RCSB
Revision 1.0	Apr 17, 2019	Provider: repository / Type: Initial release
Revision 1.1	Apr 24, 2019	Group: Data collection / Database references / Category: citation / citation_author Item: _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2	Dec 18, 2019	Group: Author supporting evidence / Other / Category: atom_sites / pdbx_audit_support Item: _atom_sites.fract_transf_matrix[1][1] / _atom_sites.fract_transf_matrix[2][2] / _atom_sites.fract_transf_matrix[3][3] / _pdbx_audit_support.funding_organization