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TitleEndogenous ligand recognition and structural transition of a human PTH receptor.
Journal, issue, pagesMol Cell, Vol. 82, Issue 18, Page 3468-33483.e5, Year 2022
Publish dateSep 15, 2022
AuthorsKazuhiro Kobayashi / Kouki Kawakami / Tsukasa Kusakizako / Hirotake Miyauchi / Atsuhiro Tomita / Kan Kobayashi / Wataru Shihoya / Keitaro Yamashita / Tomohiro Nishizawa / Hideaki E Kato / Asuka Inoue / Osamu Nureki /
PubMed AbstractEndogenous parathyroid hormone (PTH) and PTH-related peptide (PTHrP) bind to the parathyroid hormone receptor 1 (PTH1R) and activate the stimulatory G-protein (Gs) signaling pathway. Intriguingly, ...Endogenous parathyroid hormone (PTH) and PTH-related peptide (PTHrP) bind to the parathyroid hormone receptor 1 (PTH1R) and activate the stimulatory G-protein (Gs) signaling pathway. Intriguingly, the two ligands have distinct signaling and physiological properties: PTH evokes prolonged Gs activation, whereas PTHrP evokes transient Gs activation with reduced bone-resorption effects. The distinct molecular actions are ascribed to the differences in ligand recognition and dissociation kinetics. Here, we report cryoelectron microscopic structures of six forms of the human PTH1R-Gs complex in the presence of PTH or PTHrP at resolutions of 2.8 -4.1 Å. A comparison of the PTH-bound and PTHrP-bound structures reveals distinct ligand-receptor interactions underlying the ligand affinity and selectivity. Furthermore, five distinct PTH-bound structures, combined with computational analyses, provide insights into the unique and complex process of ligand dissociation from the receptor and shed light on the distinct durations of signaling induced by PTH and PTHrP.
External linksMol Cell / PubMed:35932760
MethodsEM (single particle)
Resolution2.8 - 4.1 Å
Structure data

EMDB-32141, PDB-7vvj:
PTHrP-bound human PTH1R in complex with Gs
Method: EM (single particle) / Resolution: 3.2 Å

EMDB-32142, PDB-7vvk:
PTH-bound human PTH1R in complex with Gs (class1)
Method: EM (single particle) / Resolution: 3.3 Å

EMDB-32143, PDB-7vvl:
PTH-bound human PTH1R in complex with Gs (class2)
Method: EM (single particle) / Resolution: 2.8 Å

EMDB-32144, PDB-7vvm:
PTH-bound human PTH1R in complex with Gs (class3)
Method: EM (single particle) / Resolution: 3.2 Å

EMDB-32145, PDB-7vvn:
PTH-bound human PTH1R in complex with Gs (class4)
Method: EM (single particle) / Resolution: 3.8 Å

EMDB-32146, PDB-7vvo:
PTH-bound human PTH1R in complex with Gs (class5)
Method: EM (single particle) / Resolution: 4.1 Å

Chemicals

ChemComp-HOH:
WATER

Source
  • homo sapiens (human)
  • rattus norvegicus (Norway rat)
  • bos taurus (cattle)
  • unidentified (others)
KeywordsSIGNALING PROTEIN / G protein-coupled receptor / membrane protein

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