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Structural insights into ligand recognition and selectivity of somatostatin receptors.

Zhao W, Han S, Qiu N, Feng W, Lu M, Zhang W, Wang M, Zhou Q, Chen S, Xu W, Du J, Chu X, Yi C, Dai A, Hu L, Shen MY, Sun Y, Zhang Q, Ma Y, Zhong W, Yang D, Wang MW, Wu B, Zhao Q
Cell Res (2022)
Related entries: 7xmr, 7xms, 7xmt, 7xn9

Cited: 10 times
EuropePMC logo PMID: 35739238

Abstract

Somatostatin receptors (SSTRs) play versatile roles in inhibiting the secretion of multiple hormones such as growth hormone and thyroid-stimulating hormone, and thus are considered as targets for treating multiple tumors. Despite great progress made in therapeutic development against this diverse receptor family, drugs that target SSTRs still show limited efficacy with preferential binding affinity and conspicuous side-effects. Here, we report five structures of SSTR2 and SSTR4 in different states, including two crystal structures of SSTR2 in complex with a selective peptide antagonist and a non-peptide agonist, respectively, a cryo-electron microscopy (cryo-EM) structure of Gi1-bound SSTR2 in the presence of the endogenous ligand SST-14, as well as two cryo-EM structures of Gi1-bound SSTR4 in complex with SST-14 and a small-molecule agonist J-2156, respectively. By comparison of the SSTR structures in different states, molecular mechanisms of agonism and antagonism were illustrated. Together with computational and functional analyses, the key determinants responsible for ligand recognition and selectivity of different SSTR subtypes and multiform binding modes of peptide and non-peptide ligands were identified. Insights gained in this study will help uncover ligand selectivity of various SSTRs and accelerate the development of new molecules with better efficacy by targeting SSTRs.

Articles - 7xna mentioned but not cited (2)

  1. Identification of a Novel SSTR3 Full Agonist for the Treatment of Nonfunctioning Pituitary Adenomas. Modena D, Moras ML, Sandrone G, Stevenazzi A, Vergani B, Dasgupta P, Kliever A, Gulde S, Marangelo A, Schillmaier M, Luque RM, Bäuerle S, Pellegata NS, Schulz S, Steinkühler C. Cancers (Basel) 15 3453 (2023)
  2. Molecular simulations of SSTR2 dynamics and interaction with ligands. Gervasoni S, Guccione C, Fanti V, Bosin A, Cappellini G, Golosio B, Ruggerone P, Malloci G. Sci Rep 13 4768 (2023)


Reviews citing this publication (2)

  1. CHARMM-GUI Membrane Builder: Past, Current, and Future Developments and Applications. Feng S, Park S, Choi YK, Im W. J Chem Theory Comput 19 2161-2185 (2023)
  2. Novel emphasis on somatostatinergic system in retinal ganglion cell neuroresilience. Catalani E, Cervia D. Neural Regen Res 19 148-149 (2024)

Articles citing this publication (6)

  1. Molecular basis for the selective G protein signaling of somatostatin receptors. Chen S, Teng X, Zheng S. Nat Chem Biol 19 133-140 (2023)
  2. Prospect of acromegaly therapy: molecular mechanism of clinical drugs octreotide and paltusotine. Zhao J, Fu H, Yu J, Hong W, Tian X, Qi J, Sun S, Zhao C, Wu C, Xu Z, Cheng L, Chai R, Yan W, Wei X, Shao Z. Nat Commun 14 962 (2023)
  3. In Vitro and In Silico Investigation of BCI Anticancer Properties and Its Potential for Chemotherapy-Combined Treatments. Marciniak B, Kciuk M, Mujwar S, Sundaraj R, Bukowski K, Gruszka R. Cancers (Basel) 15 4442 (2023)
  4. Interaction of Radiopharmaceuticals with Somatostatin Receptor 2 Revealed by Molecular Dynamics Simulations. Gervasoni S, Öztürk I, Guccione C, Bosin A, Ruggerone P, Malloci G. J Chem Inf Model 63 4924-4933 (2023)
  5. Therapeutic Effect of a Latent Form of Cortistatin in Experimental Inflammatory and Fibrotic Disorders. Campos-Salinas J, Barriga M, Delgado M. Pharmaceutics 14 2785 (2022)
  6. Transcriptome analysis of hypothalamus and pituitary tissues reveals genetic mechanisms associated with high egg production rates in Changshun green-shell laying hens. Xu W, Mu R, Gegen T, Ran T, Wu Q, Wen D, Wang F, Chen Z. BMC Genomics 24 792 (2023)


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