scholarly journals Dynamics-Derived Insights into Complex Formation between the CXCL8 Monomer and CXCR1 N-Terminal Domain: An NMR Study

Molecules ◽  
2018 ◽  
Vol 23 (11) ◽  
pp. 2825 ◽  
Author(s):  
Prem Joseph ◽  
Leo Spyracopoulos ◽  
Krishna Rajarathnam
Keyword(s):  
Bound States ◽  
Dynamic Properties ◽  
Bound State ◽  
Receptor Activation ◽  
Titration Calorimetry ◽  
15N Relaxation ◽  
Terminal Domain ◽  
Nmr Study ◽  
Terminal Loop ◽  
G Protein Coupled

Interleukin-8 (CXCL8), a potent neutrophil-activating chemokine, exerts its function by activating the CXCR1 receptor that belongs to class A G protein-coupled receptors (GPCRs). Receptor activation involves interactions between the CXCL8 N-terminal loop and CXCR1 N-terminal domain (N-domain) residues (Site-I) and between the CXCL8 N-terminal and CXCR1 extracellular/transmembrane residues (Site-II). CXCL8 exists in equilibrium between monomers and dimers, and it is known that the monomer binds CXCR1 with much higher affinity and that Site-I interactions are largely responsible for the differences in monomer vs. dimer affinity. Here, using backbone 15N-relaxation nuclear magnetic resonance (NMR) data, we characterized the dynamic properties of the CXCL8 monomer and the CXCR1 N-domain in the free and bound states. The main chain of CXCL8 appears largely rigid on the picosecond time scale as evident from high order parameters (S2). However, on average, S2 are higher in the bound state. Interestingly, several residues show millisecond-microsecond (ms-μs) dynamics only in the bound state. The CXCR1 N-domain is unstructured in the free state but structured with significant dynamics in the bound state. Isothermal titration calorimetry (ITC) data indicate that both enthalpic and entropic factors contribute to affinity, suggesting that increased slow dynamics in the bound state contribute to affinity. In sum, our data indicate a critical and complex role for dynamics in driving CXCL8 monomer-CXCR1 Site-I interactions.

scholarly journals Structures of full-length glycoprotein hormone receptor signaling complexes

2021 ◽  
Author(s):  
Jia Duan ◽  
Peiyu Xu ◽  
Xi Cheng ◽  
Chunyou Mao ◽  
Tristan Croll ◽  
...  
Keyword(s):  
G Protein ◽  
Conformational Changes ◽  
Transmembrane Domain ◽  
Receptor Activation ◽  
Human Reproduction ◽  
Glycoprotein Hormone ◽  
Therapeutic Drugs ◽  
Terminal Loop ◽  
Push And Pull ◽  
G Protein Coupled

Luteinizing hormone (LH) and chorionic gonadotropin (CG) are members of the glycoprotein hormone family essential to human reproduction and are important therapeutic drugs. They activate the same G protein-coupled receptor, LHCGR, by binding to the large extracellular domain (ECD). Here we report four cryo-EM structures of LHCGR, two wildtype receptor structures in the inactive and active states, and two constitutively active mutated receptor structures. The active structures are bound to CG and Gs heterotrimer, with one of the structure also containing the allosteric agonist, Org43553. The structures reveal a distinct ′push and pull′ mechanism of receptor activation, in which the ECD is pushed by the bound hormone and pulled by the extended hinge loop next to the transmembrane domain (TMD). A highly conserved 10-residue fragment (P10) from the hinge C-terminal loop at the ECD-TMD interface functions as a tethered agonist to induce conformational changes in TMD and G-protein coupling. Org43553 binds to a TMD pocket and interacts directly with P10 that further stabilizes the receptor in the active conformation. Together, these structures provide a common model for understanding glycoprotein hormone signal transduction and dysfunction, and inspire the search for clinically suitable small molecular compounds to treat endocrine diseases.

scholarly journals The ligand-bound state of a G protein-coupled receptor stabilizes the interaction of functional cholesterol molecules

2021 ◽  
Vol 62 ◽  
pp. 100059
Author(s):  
Laura Lemel ◽  
Katarzyna Nieścierowicz ◽  
M. Dolores García-Fernández ◽  
Leonardo Darré ◽  
Thierry Durroux ◽  
...  
Keyword(s):  
G Protein ◽  
Bound State ◽  
G Protein Coupled Receptor ◽  
G Protein Coupled

scholarly journals Point-Substitution of Phenylalanine Residues of 26RFa Neuropeptide: A Structure-Activity Relationship Study

Molecules ◽  
2021 ◽  
Vol 26 (14) ◽  
pp. 4312
Author(s):  
Benjamin Lefranc ◽  
Karima Alim ◽  
Cindy Neveu ◽  
Olivier Le Marec ◽  
Christophe Dubessy ◽  
...  
Keyword(s):  
Receptor Activation ◽  
Pharmacological Profile ◽  
Acid Moiety ◽  
Structural Determinants ◽  
Physiological Processes ◽  
Structure Activity ◽  
Peptide Derivatives ◽  
Targeting Peptide ◽  
G Protein Coupled

26RFa is a neuropeptide that activates the rhodopsin-like G protein-coupled receptor QRFPR/GPR103. This peptidergic system is involved in the regulation of a wide array of physiological processes including feeding behavior and glucose homeostasis. Herein, the pharmacological profile of a homogenous library of QRFPR-targeting peptide derivatives was investigated in vitro on human QRFPR-transfected cells with the aim to provide possible insights into the structural determinants of the Phe residues to govern receptor activation. Our work advocates to include in next generations of 26RFa(20–26)-based QRFPR agonists effective substitutions for each Phe unit, i.e., replacement of the Phe22 residue by a constrained 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid moiety, and substitution of both Phe24 and Phe26 by their para-chloro counterpart. Taken as a whole, this study emphasizes that optimized modifications in the C-terminal part of 26RFa are mandatory to design selective and potent peptide agonists for human QRFPR.

scholarly journals Bound states of a Klein–Gordon particle in the presence of a smooth potential well

2020 ◽  
Vol 35 (23) ◽  
pp. 2050140
Author(s):  
Eduardo López ◽  
Clara Rojas
Keyword(s):  
Bound States ◽  
Gordon Equation ◽  
Bound State ◽  
Potential Well ◽  
One Dimensional ◽  
Smooth Potential ◽  
Klein Gordon ◽  
The One ◽  
Potential Parameters ◽  
Klein Gordon Equation

We solve the one-dimensional time-independent Klein–Gordon equation in the presence of a smooth potential well. The bound state solutions are given in terms of the Whittaker [Formula: see text] function, and the antiparticle bound state is discussed in terms of potential parameters.

scholarly journals A Structural Insight into the Reorientation of Transmembrane Domains 3 and 5 during Family A G Protein-Coupled Receptor Activation

2010 ◽  
Vol 79 (2) ◽  
pp. 262-269 ◽  
Author(s):  
Kamonchanok Sansuk ◽  
Xavier Deupi ◽  
Ivan R. Torrecillas ◽  
Aldo Jongejan ◽  
Saskia Nijmeijer ◽  
...  
Keyword(s):  
G Protein ◽  
Receptor Activation ◽  
Transmembrane Domains ◽  
G Protein Coupled Receptor ◽  
Structural Insight ◽  
G Protein Coupled ◽  
Insight Into

Conformational dynamics and thermodynamics of protein–ligand binding studied by NMR relaxation

2012 ◽  
Vol 40 (2) ◽  
pp. 419-423 ◽  
Author(s):  
Mikael Akke
Keyword(s):  
Ligand Binding ◽  
Bound States ◽  
Conformational Dynamics ◽  
Nmr Relaxation ◽  
Titration Calorimetry ◽  
Conformational Entropy ◽  
Chain Order ◽  
Ligand Interactions ◽  
Galectin 3 ◽  
Relaxation Experiments

Protein conformational dynamics can be critical for ligand binding in two ways that relate to kinetics and thermodynamics respectively. First, conformational transitions between different substates can control access to the binding site (kinetics). Secondly, differences between free and ligand-bound states in their conformational fluctuations contribute to the entropy of ligand binding (thermodynamics). In the present paper, I focus on the second topic, summarizing our recent results on the role of conformational entropy in ligand binding to Gal3C (the carbohydrate-recognition domain of galectin-3). NMR relaxation experiments provide a unique probe of conformational entropy by characterizing bond-vector fluctuations at atomic resolution. By monitoring differences between the free and ligand-bound states in their backbone and side chain order parameters, we have estimated the contributions from conformational entropy to the free energy of binding. Overall, the conformational entropy of Gal3C increases upon ligand binding, thereby contributing favourably to the binding affinity. Comparisons with the results from isothermal titration calorimetry indicate that the conformational entropy is comparable in magnitude to the enthalpy of binding. Furthermore, there are significant differences in the dynamic response to binding of different ligands, despite the fact that the protein structure is virtually identical in the different protein–ligand complexes. Thus both affinity and specificity of ligand binding to Gal3C appear to depend in part on subtle differences in the conformational fluctuations that reflect the complex interplay between structure, dynamics and ligand interactions.

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