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TitleStructure-based design of non-hypertrophic apelin receptor modulator.
Journal, issue, pagesCell, Vol. 187, Issue 6, Page 1460-1475.e20, Year 2024
Publish dateMar 14, 2024
AuthorsWei-Wei Wang / Su-Yu Ji / Wenjia Zhang / Junxia Zhang / Chenxi Cai / Rubi Hu / Shao-Kun Zang / Luwei Miao / Haomang Xu / Li-Nan Chen / Zongkuai Yang / Jia Guo / Jiao Qin / Dan-Dan Shen / Ping Liang / Yan Zhang / Yan Zhang /
PubMed AbstractApelin is a key hormone in cardiovascular homeostasis that activates the apelin receptor (APLNR), which is regarded as a promising therapeutic target for cardiovascular disease. However, adverse ...Apelin is a key hormone in cardiovascular homeostasis that activates the apelin receptor (APLNR), which is regarded as a promising therapeutic target for cardiovascular disease. However, adverse effects through the β-arrestin pathway limit its pharmacological use. Here, we report cryoelectron microscopy (cryo-EM) structures of APLNR-G complexes bound to three agonists with divergent signaling profiles. Combined with functional assays, we have identified "twin hotspots" in APLNR as key determinants for signaling bias, guiding the rational design of two exclusive G-protein-biased agonists WN353 and WN561. Cryo-EM structures of WN353- and WN561-stimulated APLNR-G protein complexes further confirm that the designed ligands adopt the desired poses. Pathophysiological experiments have provided evidence that WN561 demonstrates superior therapeutic effects against cardiac hypertrophy and reduced adverse effects compared with the established APLNR agonists. In summary, our designed APLNR modulator may facilitate the development of next-generation cardiovascular medications.
External linksCell / PubMed:38428423
MethodsEM (single particle)
Resolution2.6 - 3.2 Å
Structure data

38794

8xzf

EMDB-38794, PDB-8xzf:
Cryo-EM structure of the WN561-bound human APLNR-Gi complex
Method: EM (single particle) / Resolution: 3.0 Å

38795

8xzg

EMDB-38795, PDB-8xzg:
Cryo-EM structure of the [Pyr1]-apelin-13-bound human APLNR-Gi complex
Method: EM (single particle) / Resolution: 3.2 Å

38796

8xzh

EMDB-38796, PDB-8xzh:
Cryo-EM structure of the MM07-bound human APLNR-Gi complex
Method: EM (single particle) / Resolution: 2.6 Å

38797

8xzi

EMDB-38797, PDB-8xzi:
Cryo-EM structure of the CMF-019-bound human APLNR-Gi complex
Method: EM (single particle) / Resolution: 2.7 Å

38798

8xzj

EMDB-38798, PDB-8xzj:
Cryo-EM structure of the WN353-bound human APLNR-Gi complex
Method: EM (single particle) / Resolution: 3.0 Å

Chemicals

PDB-1d5n:
CRYSTAL STRUCTURE OF E. COLI MNSOD AT 100K

Source
  • homo sapiens (human)
  • synthetic construct (others)
KeywordsMEMBRANE PROTEIN / APLNR / Class A GPCR / Synthetic peptide / apelin / Structural protein / MM07 / Cyclic peptide / CMF-019 / G-protein-biased small molecule agonist

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