Cryo-EM structure of the human somatostatin receptor 2 complex with its agonist somatostatin delineates the ligand-binding specificity

Heo, Yunseok; Lee, Yoonjung; Jeon, Ye-Eun; Yun, Ji-Hye; Ishimoto, Naito; Woo, Hyeonuk; Park, Sam-Yong; Song, Ji-Joon; Lee, Weontae

doi:10.7554/elife.76823

Cited by 15 publications

(8 citation statements)

References 26 publications

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“…Furthermore, the Lys residue in each ligand (K9 for SST14 and K5 for both OCT and CYN) stably interacts with D122 3.32 , Q126 3.36 and Y302 7.43 , as already reported in literature based on structural data 25 . Differently, we found that the Trp residue (W8 for SST14 and D W4 for both OCT and CYN) maintains the interaction with I177 4.60 , looses that with F208 5.38 , and gains an additional one, Q126 3.36 (for SST14 and OCT) or D122 3.32 (for CYN).…”

Section: Sstr2 Agonists and Antagonist Show Different Interaction Pat...supporting

confidence: 77%

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Molecular simulations of SSTR2 dynamics and interaction with ligands

Gervasoni

Guccione

Fanti

et al. 2023

Sci Rep

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The cyclic peptide hormone somatostatin regulates physiological processes involved in growth and metabolism, through its binding to G-protein coupled somatostatin receptors. The isoform 2 (SSTR2) is of particular relevance for the therapy of neuroendocrine tumours for which different analogues to somatostatin are currently in clinical use. We present an extensive and systematic computational study on the dynamics of SSTR2 in three different states: active agonist-bound, inactive antagonist-bound and apo inactive. We exploited the recent burst of SSTR2 experimental structures to perform μs-long multi-copy molecular dynamics simulations to sample conformational changes of the receptor and rationalize its binding to different ligands (the agonists somatostatin and octreotide, and the antagonist CYN154806). Our findings suggest that the apo form is more flexible compared to the holo ones, and confirm that the extracellular loop 2 closes upon the agonist octreotide but not upon the antagonist CYN154806. Based on interaction fingerprint analyses and free energy calculations, we found that all peptides similarly interact with residues buried into the binding pocket. Conversely, specific patterns of interactions are found with residues located in the external portion of the pocket, at the basis of the extracellular loops, particularly distinguishing the agonists from the antagonist. This study will help in the design of new somatostatin-based compounds for theranostics of neuroendocrine tumours.

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Section: Sstr2 Agonists and Antagonist Show Different Interaction Pat...supporting

confidence: 77%

“…Robertson and co-workers released the first cryo-EM structures of SSTR2 bound with SST14 and octreotide 24 . New structures soon followed, also in complex with other ligands 14,15,25,26 and one in the apo inactive form 27 (Table S1). An important feature of the SSTR2…”

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confidence: 99%

Molecular simulations of SSTR2 dynamics and interaction with ligands

Gervasoni

Guccione

Fanti

et al. 2023

Sci Rep

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“…Interestingly, previous works reported the key role of Tyr205 5.35 and Ile195 in the interaction of SSTR2 with SST14 and octreotide (through F7 and F3, respectively), and it was also pointed out that these two residues can contribute to the selectivity of the different SSTR isoforms. 20 , 21 , 13 , 23 , 28 Furthermore, Phe294 7.35 and Ser279 6.58 (belonging to the hydrophobic sub-pocket constituted by TM6–7 and ECL3 13 ) seem to be involved in isoform selectivity as well, 23 and we found consistently their interaction with the disulfide bridge featured by all compounds (75/70% for 68 Ga-DOTATOC, 86/81% for 68 Ga-DOTATATE, 77/41% for 68 Ga-DOTANOC). Although the aforementioned interactions are conserved, we noticed some differences in the persistence of the DOTA-Tyr205 5.35 interaction.…”

Section: Resultsmentioning

confidence: 99%

Interaction of Radiopharmaceuticals with Somatostatin Receptor 2 Revealed by Molecular Dynamics Simulations

Gervasoni

Ozturk

Guccione

et al. 2023

J. Chem. Inf. Model.

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The development of drugs targeting somatostatin receptor 2 (SSTR2), generally overexpressed in neuroendocrine tumors, is focus of intense research. A few molecules in conjugation with radionuclides are in clinical use for both diagnostic and therapeutic purposes. These radiopharmaceuticals are composed of a somatostatin analogue biovector conjugated to a chelator moiety bearing the radionuclide. To date, despite valuable efforts, a detailed molecular-level description of the interaction of radiopharmaceuticals in complex with SSTR2 has not yet been accomplished. Therefore, in this work, we carefully analyzed the key dynamical features and detailed molecular interactions of SSTR2 in complex with six radiopharmaceutical compounds selected among the few already in use ( 64 Cu/ 68 Ga-DOTATATE, 68 Ga-DOTATOC, 64 Cu-SARTATE) and some in clinical development ( 68 Ga-DOTANOC, 64 Cu-TETATATE). Through molecular dynamics simulations and exploiting recently available structures of SSTR2, we explored the influence of the different portions of the compounds (peptide, radionuclide, and chelator) in the interaction with the receptor. We identified the most stable binding modes and found distinct interaction patterns characterizing the six compounds. We thus unveiled detailed molecular interactions crucial for the recognition of this class of radiopharmaceuticals. The microscopically well-founded analysis presented in this study provides guidelines for the design of new potent ligands targeting SSTR2.

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“…The heterotrimeric mGαq iN /Gβ1γ2 was designed as previously described in mini-Gαq/Gβ1γ2 [ 20 ]. Single chain antibody scFv16 containing GP67 secretion signal sequence was also inserted into pFastBac1 vector [ 21 ].…”

Section: Methodsmentioning

confidence: 99%

Structure of the human galanin receptor 2 bound to galanin and Gq reveals the basis of ligand specificity and how binding affects the G-protein interface

et al. 2022

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Galanin is a neuropeptide expressed in the central and peripheral nervous systems, where it regulates various processes including neuroendocrine release, cognition, and nerve regeneration. Three G-protein coupled receptors (GPCRs) for galanin have been discovered, which is the focus of efforts to treat diseases including Alzheimer’s disease, anxiety, and addiction. To understand the basis of the ligand preferences of the receptors and to assist structure-based drug design, we used cryo-electron microscopy (cryo-EM) to solve the molecular structure of GALR2 bound to galanin and a cognate heterotrimeric G-protein, providing a molecular view of the neuropeptide binding site. Mutant proteins were assayed to help reveal the basis of ligand specificity, and structural comparison between the activated GALR2 and inactive hβ2AR was used to relate galanin binding to the movements of transmembrane (TM) helices and the G-protein interface.

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Cryo-EM structure of the human somatostatin receptor 2 complex with its agonist somatostatin delineates the ligand-binding specificity

Cited by 15 publications

References 26 publications

Molecular simulations of SSTR2 dynamics and interaction with ligands

Molecular simulations of SSTR2 dynamics and interaction with ligands

Interaction of Radiopharmaceuticals with Somatostatin Receptor 2 Revealed by Molecular Dynamics Simulations

Structure of the human galanin receptor 2 bound to galanin and Gq reveals the basis of ligand specificity and how binding affects the G-protein interface

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