Prospect of acromegaly therapy: molecular mechanism of clinical drugs octreotide and paltusotine

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Feb. 21, 2023

Abstract Somatostatin receptor 2 (SSTR2) is highly expressed in neuroendocrine tumors and represents as a therapeutic target. Several peptide analogs mimicking the endogenous ligand somatostatin are available for clinical use, but poor effects occur subset of patients, which may be correlated with subtype selectivity or cell surface expression. Here, we clarify signal bias profiles first-generation drug octreotide new-generation small molecule paltusotine by evaluating their pharmacological characteristics. We then perform cryo-electron microscopy analysis SSTR2-Gi complexes to determine how drugs activate SSTR2 selective manner. In this work, decipher mechanism recognition, property sensing paltusotine, aid designing specific against tumors.

Language: Английский

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Structural insights into the activation of somatostatin receptor 2 by cyclic SST analogues

Cell Discovery, Journal Year: 2022, Volume and Issue: 8(1)

Published: May 20, 2022

The endogenous cyclic tetradecapeptide SST14 was reported to stimulate all five somatostatin receptors (SSTR1-5) for hormone release, neurotransmission, cell growth arrest and cancer suppression. Two SST14-derived short SST analogues (lanreotide or octreotide) with improved stability longer lifetime were developed as drugs preferentially activate SSTR2 treat acromegalia neuroendocrine tumors. Here, cryo-EM structures of the human SSTR2-Gi complex bound SST14, octreotide lanreotide determined at resolutions 2.85 Å, 2.97 2.87 respectively. Structural functional analysis revealed that interactions between β-turn residues in transmembrane ligand-binding pocket are crucial receptor binding stimulation two octapeptides. Additionally, Q102

Language: Английский

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AlphaFold-predicted protein structures and small-angle X-ray scattering: insights from an extended examination of selected data in the Small-Angle Scattering Biological Data Bank

Journal of Applied Crystallography, Journal Year: 2023, Volume and Issue: 56(4), P. 910 - 926

Published: July 4, 2023

By providing predicted protein structures from nearly all known sequences, the artificial intelligence program AlphaFold (AF) is having a major impact on structural biology. While stunning accuracy has been achieved for many folding units, unstructured regions and arrangement of potentially flexible linkers connecting structured domains present challenges. Focusing single-chain without prosthetic groups, an earlier comparison features derived small-angle X-ray scattering (SAXS) data taken Small-Angle Scattering Biological Data Bank (SASBDB) extended to those calculated using corresponding AF-predicted structures. Selected SASBDB entries were carefully examined ensure that they represented monodisperse solutions had sufficient statistical precision q resolution reliable evaluation. Three examples identified where there clear evidence single structure cannot account experimental SAXS data. Instead, excellent agreement found with ensemble models generated by allowing between high-confidence domains. A pool representative was Monte Carlo method adjusts backbone dihedral allowed angles along regions. fast modelling employed optimizes fit pair distance distribution functions [ P ( r ) versus ] intensity profiles I computed their counterparts. These results highlight complementarity AF prediction, solution molecular dynamics/conformational sampling proteins both

Language: Английский

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Structure and Function of Somatostatin and Its Receptors in Endocrinology

Endocrine Reviews, Journal Year: 2024, Volume and Issue: 46(1), P. 26 - 42

Published: Aug. 8, 2024

Abstract Somatostatin analogs, such as octreotide, lanreotide, and pasireotide, which function somatostatin receptor ligands (SRLs), are the main drugs used for treatment of acromegaly. These also important molecules radiation therapy imaging neuroendocrine tumors. receptors (SSTRs) canonical G protein-coupled proteins that play a role in metabolism, growth, pathological conditions hormone disorders, neurological diseases, cancers. Cryogenic electron microscopy combined with protein structure prediction platform AlphaFold has been to determine 3-dimensional structures many proteins. Recently, several groups published series papers illustrating SSTR2, including inactive/activated SSTR2-G complex bound different ligands. The results revealed residues contribute ligand binding pocket demonstrated Trp8-Lys9 (the W-K motif) analogs is key motif stabilizing bottom part pocket. In this review, we discuss recent findings related structural analysis SSTRs SRLs, relationships between data clinical findings, future development novel structure-based therapies.

Language: Английский

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Unraveling the Molecular Architecture of Mosquito D1‐Like Dopamine Receptors: Insights Into Ligand Binding and Structural Dynamics for Insecticide Development

Proteins Structure Function and Bioinformatics, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 18, 2025

ABSTRACT Vector‐borne diseases pose a severe threat to human life, contributing significantly global mortality. Understanding the structure–function relationship of vector proteins is pivotal for effective insecticide development due their involvement in drug resistance and disease transmission. This study reports structural dynamic features D1‐like dopamine receptors (DARs) disease‐causing mosquito species, such as Aedes aegypti , Culex quinquefasciatus Anopheles gambiae stephensi . Through molecular modeling simulations, we describe common fold DARs within G‐protein–coupled receptor family, highlighting importance an orthosteric enlarged binding pocket. The pocket, resembling cage‐like structure, situated ~15 Å deep protein, with two serine residues forming roof aspartate residue, along conserved water molecules (W1 W2), floor. side walls are composed phenylalanine on one valine residue other. antagonist site, pocket (EBP) near entrance cavity, can accommodate ligands varying sizes. energy observed be ~2–3 kcal/mol higher than that amitriptyline, asenapine, flupenthixol DARs. These bind EBP, which obstructs movement toward active thereby inhibiting signal transduction. Our findings elucidate architecture pockets versatility accommodating diverse ligands, providing foundational framework future development.

Language: Английский

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Side-by-Side Comparison of the In Vivo Performance of [²¹²Pb]Pb-DOTAMTATE and Other SSTR2-Targeting Compounds

Journal of Nuclear Medicine, Journal Year: 2025, Volume and Issue: unknown, P. jnumed.124.268345 - jnumed.124.268345

Published: Jan. 30, 2025

There are numerous versions of octreotide and octreotate, including DOTAMTATE, DOTATATE, JR11, lead-specific chelator (PSC)-PEG2-TOC. These peptides, which can be either analogs or antagonists, used in nuclear medicine for diagnostic imaging targeted radionuclide therapy neuroendocrine tumors that positive somatostatin receptors (SSTRs). Despite their structural targeting similarities, they have distinct properties clinical uses. We aimed to perform an extensive preclinical comparison all these with ²¹²Pb, directly studying pharmacokinetic overexpressing SSTR2. Methods: All SSTR2 were manufactured the DOTAM, PSC, DOTA chelators appropriate after radiolabeling ²¹²Pb. Chelation, quantification, pharmacokinetics compared side by AR42J-tumor–bearing animals. Results: findings highlight superior chelation efficiency faster kinetics DOTAM then PSC. also discovered a tumor-to-kidney area under curve ratio [²¹²Pb]Pb-DOTAMTATE over other SSTR2-targeting peptides when radiolabeled Conclusion: Taken together, results indicates has favorable tumor retention more dosimetry profile, is crucial α-therapy treating SSTR2-positive tumors.

Language: Английский

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

eLife, Journal Year: 2022, Volume and Issue: 11

Published: April 21, 2022

Somatostatin is a peptide hormone that regulates endocrine systems by binding to G-protein-coupled somatostatin receptors. receptor 2 (SSTR2) human and highly implicated in disorders, cancers, neurological diseases. Here, we report the high-resolution cryo-EM structure of full-length SSTR2 bound agonist (SST-14) complex with inhibitory G (G i ) proteins. Our structural mutagenesis analyses show seven transmembrane helices form deep pocket for ligand recognizes conserved Trp-Lys motif SST-14 at bottom pocket. Furthermore, our sequence analysis combined AlphaFold modeled structures other SSTR isoforms provide basis mechanism which family proteins specifically interact their cognate ligands. This work provides first glimpse into molecular recognition receptors crucial resource develop therapeutics targeting

Language: Английский

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Hidden Structural States of Proteins Revealed by Conformer Selection with AlphaFold-NMR

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: June 30, 2024

Abstract Recent advances in molecular modeling using deep learning can revolutionize our understanding of dynamic protein structures. NMR is particularly well-suited for determining features biomolecular The conventional process structures from experimental data involves its representation as conformation-dependent restraints, followed by generation structural models guided these spatial restraints. Here we describe an alternative approach: generating a distribution realistic conformational artificial intelligence-(AI-) based methods and then selecting the sets conformers that best explain data. We applied this selection approach to redetermine solution structure enzyme Gaussia luciferase. First, generated diverse set conformer AlphaFold2 (AF2) with enhanced sampling protocol. best-fit NOESY chemical shift were selected Bayesian scoring metric. resulting include both published standard AF2 model without sampling. This “AlphaFold-NMR” protocol also “open” state fits nearly well overall but accounts some not consistent first “closed” state; while other second are state. differs primarily position thumb-shaped loop between α-helices H5 H6, revealing cryptic surface pocket. These states Gluc supported “double recall” analysis models. Additional indicated backbone indicating partially-disordered conformations C-terminal segment. Considered multistate ensemble, multiple together fit better than “restraint-based” provide novel insights into structure-dynamic-function relationships. study demonstrates potential AI-based generate ensembles restraint satisfaction protocols determination.

Language: Английский

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Molecular simulations of SSTR2 dynamics and interaction with ligands

Scientific Reports, Journal Year: 2023, Volume and Issue: 13(1)

Published: March 23, 2023

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

Language: Английский

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

Journal of Chemical Information and Modeling, Journal Year: 2023, Volume and Issue: 63(15), P. 4924 - 4933

Published: July 19, 2023

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

Language: Английский

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