Bradykinin B2 receptor signaling: Structural and functional characterization of the C‐terminus

Piserchio, Andrea; Zelesky, Veronica; Yu, Jun; Taylor, Linda; Polgár, Péter; Mierke, Dale F.

doi:10.1002/bip.20220

Cited by 18 publications

(22 citation statements)

References 18 publications

(37 reference statements)

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“…NMR in conjunction with CD spectroscopy confirmed the presence of an H8 for the CB 1 andCB 2 receptors, the Ste2p receptor, the β 1 and β 2 receptors, the angiotensin AT 1A receptor, and the bradykinin B 2 receptor in detergent [70–75]. In Fig.…”

Section: Determination Of the 3d Structure Of Gpcrsmentioning

confidence: 93%

Unraveling the Structure and Function of G Protein-Coupled Receptors Through NMR Spectroscopy

Tikhonova¹,

Costanzi²

2009

CPD

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G protein-coupled receptors (GPCRs) are a large superfamily of signaling proteins expressed on the plasma membrane. They are involved in a wide range of physiological processes and, therefore, are exploited as drug targets in a multitude of therapeutic areas. In this extent, knowledge of structural and functional properties of GPCRs may greatly facilitate rational design of modulator compounds. Solution and solid-state nuclear magnetic resonance (NMR) spectroscopy represents a powerful method to gather atomistic insights into protein structure and dynamics. In spite of the difficulties inherent the solution of the structure of membrane proteins through NMR, these methods have been successfully applied, sometimes in combination with molecular modeling, to the determination of the structure of GPCR fragments, the mapping of receptor-ligand interactions, and the study of the conformational changes associated with the activation of the receptors. In this review, we provide a summary of the NMR contributions to the study of the structure and function of GPCRs, also in light of the published crystal structures. KeywordsG protein-coupled receptors (GPCRs); NMR; three-dimensional structures; ligand recognition; receptor activation G protein-coupled receptors (GPCRs), also known as seven transmembrane-spanning receptors (7TMRs), are a large superfamily of signaling proteins expressed on the plasma membrane that function as receivers for extracellular stimuli [1]. About 1000 GPCRs have been identified in the human genome [2]. Since their signaling is involved in numerous physiological functions and pathological conditions, GPCRs constitute the molecular target of a significant percentage of the currently marketed drugs. Moreover, many additional members of the superfamily have been identified as potential targets for the treatment of a variety of diseases and are the object of substantial drug discovery efforts. From the molecular point of view, all GPCRs share a common molecular architecture, being composed of a single polypeptide chain folded into a bundle of seven α-helical transmembrane domains (TMs) connected by three extracellular and three intracellular loops (ELs and ILs). The N-terminus is located in the extracellular space, while the C-terminus is in the cytosol (Fig. (1)).Given that structure-based drug discovery is an efficient method to rationally design novel drugs and improve the properties of old drugs, the scientific community has been striving for a long time to shed light onto the elusive structure-function relationships of GPCRs employing a variety of direct biophysical and indirect biochemical methods [3]. The most direct method that has been used is X-ray crystallography. However, up until now, this technique has been *address for correspondence: stefanoc@mail.nih.gov. NIH Public Access Author ManuscriptCurr Pharm Des. Author manuscript; available in PMC 2010 January 5. Published in final edited form as:Curr Pharm Des. 2009 ; 15(35): 4003-4016. NIH-PA Author ManuscriptNIH-PA Author Manuscript...

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Section: Determination Of the 3d Structure Of Gpcrsmentioning

confidence: 93%

Unraveling the Structure and Function of G Protein-Coupled Receptors Through NMR Spectroscopy

Tikhonova¹,

Costanzi²

2009

CPD

View full text Add to dashboard Cite

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“…After B 2 receptors are activated, they undergo a rapid internalization, resulting in a desensitization of the receptors [108]. Structure scanning analysis provides evidence that only those within the ␣-helices of C-terminus are important for kinin B 2 receptor signaling [109].…”

Section: Kinin Receptors and Ahrmentioning

confidence: 99%

MAPK/NF-κB-dependent upregulation of kinin receptors mediates airway hyperreactivity: A new perspective for the treatment

Zhang

Cardell

Edvinsson

et al. 2013

Pharmacological Research

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“…This complex has been postulated to comprise a G αq ‐binding site. NMR studies find that the bradykinin receptor, which also signals through G αq , also has an H9 (Piserchio et al. 2005).…”

Section: H9 and The Remainder Of The Cb1 Carboxyl‐terminusmentioning

confidence: 99%

The cannabinoid type‐1 receptor carboxyl‐terminus, more than just a tail

Stadel

Ahn

Kendall

2011

Journal of Neurochemistry

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J. Neurochem. (2011) 117, 1–18. Abstract The cannabinoid type‐1 (CB1) receptor is a G protein‐coupled receptor that binds the main active ingredient of marijuana, Δ9‐tetrahydrocannabinol, and has been implicated in several disease states, including drug addiction, anxiety, depression, obesity, and chronic pain. In the two decades since the discovery of CB1, studies at the molecular level have centered on the transmembrane core. This interest has now expanded as we discover that other regions of CB1, including the CB1 carboxyl‐terminus, have critical structures that are important for CB1 activity and regulation. Following the recent description of the three dimensional structure of the full‐length CB1 carboxyl‐terminal tail [Biopolymers (2009) vol. 91, pp. 565–573], several residues and structural motifs including two α‐helices (termed H8 and H9) have been postulated to interact with common G protein‐coupled receptor accessory proteins, such as G‐proteins and β‐arrestins. This discourse will focus on the CB1 carboxyl‐terminus; our current understanding of the structural features of this region, evidence for its interaction with proteins, and the impact of structure on the binding and regulatory function of CB1 accessory proteins. The involvement of the carboxyl‐terminus in the receptor life cycle including activation, desensitization, and internalization will be highlighted.

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Bradykinin B2 receptor signaling: Structural and functional characterization of the C‐terminus

Abstract: Over the last few years the importance of the intracellular C-terminus in the signaling of G-protein coupled receptors (GPCR

Cited by 18 publications

References 18 publications

Unraveling the Structure and Function of G Protein-Coupled Receptors Through NMR Spectroscopy

Unraveling the Structure and Function of G Protein-Coupled Receptors Through NMR Spectroscopy

MAPK/NF-κB-dependent upregulation of kinin receptors mediates airway hyperreactivity: A new perspective for the treatment

The cannabinoid type‐1 receptor carboxyl‐terminus, more than just a tail

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