Structure of the full-length glucagon class B G-protein-coupled receptor

Zhang, Haonan; Qiao, Anna; Yang, Dehua; Yang, Linlin; Dai, Antao; Graaf, Chris de; Reedtz-Runge, Steffen; Dharmarajan, Venkatasubramanian; Zhang, Hui; Han, Gye Won; Grant, Thomas D.; Sierra, Raymond G.; Weierstall, Uwe; Nelson, Garrett; Liu, Wei; Wu, Yanhong; Ma, Limin; Cai, Xiaoqing; Lin, Gonghua; Wu, Xiaoai; Geng, Zhi; Dong, Yuhui; Song, Gaojie; Griffin, Patrick R.; Lau, Jesper; Cherezov, Vadim; Yang, Huaiyu; Hanson, Michael A.; Stevens, Raymond C.; Zhao, Qiang; Jiang, Hualiang; Wang, Ming Wei; Wu, Beili

doi:10.1038/nature22363

Cited by 188 publications

(192 citation statements)

References 45 publications

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“…Since then, technical upgrades allowed for high-resolution X-ray data to be recorded [11], including the high-resolution structure of cathepsin B bound to its native inhibitor [12], a potential drug target against sleeping sickness. Additionally, structures of several biomedically important G protein-coupled receptors (GPCRs) have been successfully solved with XFELs [13–19], including the rhodopsin-arrestin complex [20]. Furthermore, recent demonstrations of the possibility of de novo phasing [21–26] as well as ultra-fast time-resolved studies of proteins [27–30] and nucleic acids [31] further unveil the potential of XFELs for structural biology.…”

Section: Xfels Opened Up New Era In Crystallographymentioning

confidence: 99%

“…One of the most successful applications of SFX has been the structural study of membrane proteins using LCP as the crystallization and crystal delivery medium, which led to structure determination of several GPCRs [13–19] including the signaling complex between GPCR and arrestin [20], the membrane enzyme diacylglycerol kinase [102], and the light-activated proton pump bacteriorhodopsin [103]. …”

Section: Sfx Applicationsmentioning

confidence: 99%

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A Bright Future for Serial Femtosecond Crystallography with XFELs

Johansson

Stauch

Ishchenko

et al. 2017

Trends in Biochemical Sciences

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128

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X-ray free electron lasers (XFELs) have potential to revolutionize macromolecular structural biology due to the unique combination of spatial coherence, extreme peak brilliance and short duration of X-ray pulses. A recently emerged serial femtosecond crystallography (SFX) approach using XFEL radiation overcomes some of the biggest hurdles of traditional crystallography related to radiation damage through the diffraction-before-destruction principle. Intense femtosecond XFEL pulses enable high-resolution room temperature structure determination of difficult to crystallize biological macromolecules, while simultaneously opening up a new era of time-resolved structural studies. Here, we review the latest developments in instrumentation, sample delivery, data analysis, crystallization methods and applications of SFX to important biological questions, and conclude with brief insights into the bright future of structural biology using XFELs.

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Section: Xfels Opened Up New Era In Crystallographymentioning

confidence: 99%

Section: Sfx Applicationsmentioning

confidence: 99%

A Bright Future for Serial Femtosecond Crystallography with XFELs

Johansson

Stauch

Ishchenko

et al. 2017

Trends in Biochemical Sciences

Self Cite

128

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“…Hence, the full-length GCGR in this model appeared to exist in two states, open or closed, dependent on the hinge action of the linker region. However, GCGR crystallography solutions of the full-length receptor (PDBID: 5XEZ) using mAb1 to stabilize the ECD revealed that the linker/ stalk region was more intricate and that instead of an α-helix extension from TM1, the neck could adopt a β-strand configuration for interactions with a β-hairpin of ECL1 to form a β-sheet structure (Zhang et al 2017a). This structural detail allowed stabilization of the GCGR ECD in an inactive open state.…”

Section: Pac1 Versus Glucagon Receptormentioning

confidence: 99%

“…Perhaps not surprisingly, nearly 40% of all pharmaceutical drugs target class A receptors (Luttrell et al 2015; Zhang et al 2015). The structural solutions to the class B receptors, which encompass 15 members including CRH, glucagon, GLP-1, secretin, vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase activating polypeptide (PACAP) receptors, have lagged and the 7TM structures of only 4 members have become available only within the last 5 years (Hollenstein et al 2013; Siu et al 2013; Yang et al 2015; Jazayeri et al 2016; Jazayeri et al 2017; Liang et al 2017; Song et al 2017; Zhang et al 2017a; Zhang et al 2018). Although class B receptors are fewer in number, these receptors are increasingly being recognized as mediating some of the most critical physiological functions, including feeding and energy balance, sensory mechanisms, bone metabolism and stress responses (Harmar et al 2012; Culhane et al 2015).…”

mentioning

confidence: 99%

PAC1 Receptors: Shapeshifters in Motion

Liao

May

2018

J Mol Neurosci

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Shapeshifters, in common mythology, are entities that can undergo multiple physical transformations. As our understanding of G protein-coupled receptors (GPCRs) has accelerated and been refined over the last two decades, we now understand that GPCRs are not static proteins, but rather dynamic structures capable of moving from one posture to the next, and adopting unique functional characteristics at each transition. This model of GPCR dynamics underlies our current understanding of biased agonism-how different ligands to the same receptor can generate different intracellular signals-and constitutive receptor activity, or the level of unbound basal receptor signaling that can be attenuated by inverse agonists. From information derived from related class B receptors, we have recently modeled the structure and molecular dynamics of the full-length pituitary adenylate cyclase activating polypeptide (PACAP, Adcyap1)-selective PAC1 receptor (PAC1R, Adcyap1r1). The class B receptors are different from the class A GPCRs in part from the presence of a large extracellular domain (ECD); the transitions of the ECD along with the dynamics of the transmembrane domains (TMD or 7TM) of the PAC1R describes a series of open- and closed-state conformations that appear to identify the mechanisms for receptor activation. The PAC1R shapeshifts also have the ability of delineating the mechanisms and the design of reagents that may direct biased agonism (or antagonism) for potential therapeutics.

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“…Accordingly, these receptors are pharmacological targets for a variety of disorders including osteoporosis, hypercalcemia, type 2 diabetes, obesity, migraine and related chronic pain disorders, anxiety and depression. Despite the great pharmacological interests, only two full-length Class B receptor structures [6–8] have been determined. The three-dimensional molecular structures remain entirely or partially elusive among most Class B members.…”

Section: Introductionmentioning

confidence: 99%

Assessment of Conformational State Transitions of Class B GPCRs Using Molecular Dynamics

Liao

May

2019

Methods in Molecular Biology

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Class B G protein-coupled receptors (GPCRs) comprise a family of 15 peptide-binding members, which are crucial targets for endocrine, metabolic, and stress-related disorders. While their protein structures and dynamics remain largely unclear, computer modeling and simulations represent a promising means to help solve such puzzles. Herein, we present a basic introduction to the methodology of molecular dynamics (MD) simulations and two analytical methods to assess the conformational ensembles and transitions of Class B GPCRs, using our recent studies of the human pituitary adenylate cyclase activating polypeptide (PAC1) receptor as an example. From long MD simulations, conformational ensembles with different roles in ligand binding and receptor activation are sampled to establish four states identified as either “open” or “closed” for the PAC1 receptor. Next, the dynamical network can be applied to analyze the simulations and identify key features within each conformational ensemble, which help distinguish the ligand-bound states of the PAC1 receptor from the ligand-free one. Further, the Markov State Model has emerged as a key approach to construct the transition network and connect the GPCR ensembles, providing detailed information for the transition pathways and kinetics. For the ligand-free PAC1 receptor, the transitions within the closed states are near 10–30 times faster than the open-closed transitions, which is likely related to the activation mechanism of the receptor. Overall, long MD simulations and analyses are useful to assess conformational transitions for the Class B GPCRs and to gain mechanistic insight, which is difficult to obtain using other methods.

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Structure of the full-length glucagon class B G-protein-coupled receptor

Cited by 188 publications

References 45 publications

A Bright Future for Serial Femtosecond Crystallography with XFELs

A Bright Future for Serial Femtosecond Crystallography with XFELs

PAC1 Receptors: Shapeshifters in Motion

Assessment of Conformational State Transitions of Class B GPCRs Using Molecular Dynamics

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