Abstract:
:The pituitary adenylate cyclase-activating polypeptide type I receptor (PAC1R) belongs to the secretin receptor family and is widely distributed in the central neural system and peripheral organs. Abnormal activation of the receptor mediates trigeminovascular activation and sensitization, which is highly related to migraine, making PAC1R a potential therapeutic target. Elucidation of PAC1R activation mechanism would benefit discovery of therapeutic drugs for neuronal disorders. PAC1R activity is governed by pituitary adenylate cyclase-activating polypeptide (PACAP), known as a major vasodilator neuropeptide, and maxadilan, a native peptide from the sand fly, which is also capable of activating the receptor with similar potency. These peptide ligands have divergent sequences yet initiate convergent PAC1R activity. It is of interest to understand the mechanism of PAC1R ligand recognition and receptor activity regulation through structural biology. Here we report two near-atomic resolution cryo-EM structures of PAC1R activated by PACAP38 or maxadilan, providing structural insights into two distinct ligand binding modes. The structures illustrate flexibility of the extracellular domain (ECD) for ligands with distinct conformations, where ECD accommodates ligands in different orientations while extracellular loop 1 (ECL1) protrudes to further anchor the ligand bound in the orthosteric site. By structure-guided molecular modeling and mutagenesis, we tested residues in the ligand-binding pockets and identified clusters of residues that are critical for receptor activity. The structures reported here for the first time elucidate the mechanism of specificity and flexibility of ligand recognition and binding for PAC1R, and provide insights toward the design of therapeutic molecules targeting PAC1R.
journal_name
Cell Resjournal_title
Cell researchauthors
Wang J,Song X,Zhang D,Chen X,Li X,Sun Y,Li C,Song Y,Ding Y,Ren R,Harrington EH,Hu LA,Zhong W,Xu C,Huang X,Wang HW,Ma Ydoi
10.1038/s41422-020-0280-2subject
Has Abstractpub_date
2020-05-01 00:00:00pages
436-445issue
5eissn
1001-0602issn
1748-7838pii
10.1038/s41422-020-0280-2journal_volume
30pub_type
杂志文章相关文献
CELL RESEARCH文献大全abstract::Critical epigenetic regulation of primate embryogenesis entails DNA methylome changes. Here we report genome-wide composition, patterning, and stage-specific dynamics of DNA methylation in pre-implantation rhesus monkey embryos as well as male and female gametes studied using an optimized tagmentation-based whole-geno...
journal_title:Cell research
pub_type: 杂志文章
doi:10.1038/cr.2017.25
更新日期:2017-04-01 00:00:00
abstract::The mixed lineage kinase domain-like (MLKL) protein is a key factor in tumor necrosis factor-induced necroptosis. Recent studies on necroptosis execution revealed a commitment role of MLKL in membrane disruption. However, our knowledge of how MLKL functions on membrane remains very limited. Here we demonstrate that ML...
journal_title:Cell research
pub_type: 杂志文章
doi:10.1038/cr.2016.26
更新日期:2016-05-01 00:00:00
abstract::Human polymorphonuclear leukocytes (PMN) have been reported to completely lack of DNA-dependent protein kinase (DNA-PK) which is composed of Ku protein and the catalytic subunit DNA-PKcs, needed for nonhomologous end-joining (NHEJ) of DNA double-strand breaks. Promyelocytic HL-60 cells express a variant form of Ku res...
journal_title:Cell research
pub_type: 杂志文章
doi:10.1038/sj.cr.7290233
更新日期:2004-08-01 00:00:00
abstract::Using two-colour flow cytometry >200 antibodies submitted to the 8th International Workshop of Human Leukocyte Differentiation Antigens (HLDA8) have been analyzed for their reactivity with resting and activated CD203c+ basophils. Four antibodies either non-reactive or weakly reactive with resting basophils exhibited a...
journal_title:Cell research
pub_type: 杂志文章
doi:10.1038/sj.cr.7290301
更新日期:2005-05-01 00:00:00
abstract::Toll-Like Receptors (TLRs) play critical roles in the early innate immune response to invading pathogens by sensing microorganisms; a number of accessory molecules have been shown to assist microbial recognition by TLRs. In a recent paper in Cell Research, Yang et al. demonstrate that Mex3B is associated with TLR3 in ...
journal_title:Cell research
pub_type: 评论,杂志文章
doi:10.1038/cr.2016.29
更新日期:2016-04-01 00:00:00
abstract::Neural stem cells (NSCs) constitute the cellular basis for embryonic brain development and neurogenesis. The process is regulated by NSC niche including neighbor cells such as vascular and glial cells. Since both vascular and glial cells secrete vascular endothelial growth factor (VEGF) and basic fibroblast growth fac...
journal_title:Cell research
pub_type: 杂志文章
doi:10.1038/sj.cr.7310126
更新日期:2007-01-01 00:00:00
abstract::Generation of widely differing and specialized cell types from a single totipotent zygote involves large-scale transcriptional changes and chromatin reorganization. Pioneer transcription factors play key roles in programming the epigenome and facilitating recruitment of additional regulatory factors during successive ...
journal_title:Cell research
pub_type: 杂志文章
doi:10.1038/s41422-019-0168-1
更新日期:2019-06-01 00:00:00
abstract::DNA damage can, but does not always, induce cell death. While several pathways linking DNA damage signals to mitochondria-dependent and -independent death machineries have been elucidated, the connectivity of these pathways is subject to regulation by multiple other factors that are not well understood. We have propos...
journal_title:Cell research
pub_type: 杂志文章,评审
doi:10.1038/cr.2007.110
更新日期:2008-01-01 00:00:00
abstract::Carotenoids, a class of natural pigments found in all photosynthetic organisms, are involved in a variety of physiological processes, including coloration, photoprotection, biosynthesis of abscisic acid (ABA) and chloroplast biogenesis. Although carotenoid biosynthesis has been well studied biochemically, the genetic ...
journal_title:Cell research
pub_type: 杂志文章
doi:10.1038/cr.2007.37
更新日期:2007-05-01 00:00:00
abstract::Plant reproduction is initiated by the specification of sporocytes that form haploid spores through meiosis. A new study in Arabidopsis published in Cell Research shows how the product of sporocyteless/nozzle, a key gene in this process, partners with co-repressors and transcription factors to promote spore formation,...
journal_title:Cell research
pub_type: 评论,杂志文章
doi:10.1038/cr.2014.164
更新日期:2015-01-01 00:00:00
abstract::The term epigenetics refers to heritable changes not encoded by DNA. The organization of DNA into chromatin fibers affects gene expression in a heritable manner and is therefore one mechanism of epigenetic inheritance. Large parts of eukaryotic genomes consist of constitutively highly condensed heterochromatin, import...
journal_title:Cell research
pub_type: 杂志文章,评审
doi:10.1038/cr.2009.13
更新日期:2009-03-01 00:00:00
abstract::DNA methylation and demethylation regulate many crucial biological processes in mammals and are linked to many diseases. Active DNA demethylation is believed to be catalyzed by TET proteins and a putative DNA decarboxylase that may share some similarities in sequence, structure and catalytic mechanism with isoorotate ...
journal_title:Cell research
pub_type: 杂志文章
doi:10.1038/cr.2013.107
更新日期:2013-11-01 00:00:00
abstract::In vivo genome editing represents a powerful strategy for both understanding basic biology and treating inherited diseases. However, it remains a challenge to develop universal and efficient in vivo genome-editing tools for tissues that comprise diverse cell types in either a dividing or non-dividing state. Here, we d...
journal_title:Cell research
pub_type: 杂志文章
doi:10.1038/s41422-019-0213-0
更新日期:2019-10-01 00:00:00
abstract::The aneuploid with isochromosome or telochromosome is ideal material for exploring the position of centromere in lingkage map. For obtaining these aneuploids in rice, the primary trisomics from triplo-1 to triplo-12 and the aneuploids derived from a triploid of indica rice variety Zhongxian 3037 were carefully investi...
journal_title:Cell research
pub_type: 杂志文章
doi:10.1038/cr.1997.4
更新日期:1997-06-01 00:00:00
abstract::Endothelial progenitor cells (EPCs) participate in the processes of postnatal neovascularization and re-endothelialization in response to tissue ischemia and endothelial injury. The level of EPCs present has been found to be directly associated with the outcome of cardiovascular diseases, and could be regulated by sti...
journal_title:Cell research
pub_type: 杂志文章
doi:10.1038/cr.2008.69
更新日期:2008-07-01 00:00:00
abstract::The Hippo pathway is a signal transduction pathway that regulates organ growth, stem cell biology, regeneration and cancer. Three recent proteomic studies with Hippo pathway components uncovered extensive networks of interacting proteins revealing novel connections to cell-cell junctions, regulation by vesicle traffic...
journal_title:Cell research
pub_type: 杂志文章
doi:10.1038/cr.2014.6
更新日期:2014-02-01 00:00:00
abstract::Classical methyl-CpG binding proteins contain the conserved DNA binding motif methyl-cytosine binding domain (MBD), which preferentially binds to methylated CpG dinucleotides. These proteins serve as transcriptional repressors, mediating gene silencing via DNA cytosine methylation. Mutations in methyl-CpG binding prot...
journal_title:Cell research
pub_type: 杂志文章,评审
doi:10.1038/sj.cr.7290294
更新日期:2005-04-01 00:00:00
abstract::Recent studies on enzymes and reader proteins for histone crotonylation support a function of histone crotonylation in transcription. However, the enzyme(s) responsible for histone decrotonylation (HDCR) remains poorly defined. Moreover, it remains to be determined if histone crotonylation is physiologically significa...
journal_title:Cell research
pub_type: 杂志文章
doi:10.1038/cr.2017.68
更新日期:2017-07-01 00:00:00
abstract::By screening tobacco cDNA library with MCK1 as a probe, we isolated a cDNA clone NtCPK5 (accession number AY971376), which encodes a typical calcium-dependent protein kinase. Sequence analyses indicated that NtCPK5 is related to both CPKs and CRKs superfamilies and has all of the three conserved domains of CPKs. The b...
journal_title:Cell research
pub_type: 杂志文章
doi:10.1038/sj.cr.7290330
更新日期:2005-08-01 00:00:00
abstract::A recent paper in Nature shows that tumor exosomes expressing unique integrins can determine organotropic metastasis by preparing pre-metastatic niche through their integrins-mediated fusion with and fertilization of organ-specific resident cells. ...
journal_title:Cell research
pub_type: 评论,杂志文章
doi:10.1038/cr.2015.153
更新日期:2016-02-01 00:00:00
abstract::Hedgehog (Hh) signaling plays vital roles in animal development and tissue homeostasis, and its misregulation causes congenital diseases and several types of cancer. Suppressor of Fused (Su(fu)) is a conserved inhibitory component of the Hh signaling pathway, but how it is regulated remains poorly understood. Here we ...
journal_title:Cell research
pub_type: 杂志文章
doi:10.1038/cr.2014.29
更新日期:2014-05-01 00:00:00
abstract::The nucleotide sequence deduced from the amino acid sequence of the scorpion insectotoxin AaIT was chemically synthesized and was expressed in Escherichia coli. The authenticity of this in vitro expressed peptide was confirmed by N-terminal peptide sequencing. Two groups of bioassays, artificial diet incorporation ass...
journal_title:Cell research
pub_type: 杂志文章
doi:10.1038/sj.cr.7290120
更新日期:2002-06-01 00:00:00
abstract::Apoptosis is a complex process involving a large array of genes and mutation of any of these genes may lead to malignancy formation. Re-acquirement of FasL by tumor cells may enable them to evade the surveillance of immune system and thus contributes to the growth of tumor. Apart from traditional therapies, inducing a...
journal_title:Cell research
pub_type: 杂志文章,评审
doi:10.1038/sj.cr.7290060
更新日期:2001-03-01 00:00:00
abstract::The cytotoxic T lymphocyte antigen-4 (CTLA-4)-blocking antibody ipilimumab induces immune-mediated long-term control of metastatic melanoma in a fraction of patients. Although ipilimumab undoubtedly exerts its therapeutic effects via immunostimulation, thus far clinically useful, immunologically relevant biomarkers th...
journal_title:Cell research
pub_type: 杂志文章
doi:10.1038/cr.2015.3
更新日期:2015-02-01 00:00:00
abstract::Platelets play an essential role in hemostasis and atherothrombosis. Owing to their short storage time, there is constant demand for this life-saving blood component. In this study, we report that it is feasible to generate functional megakaryocytes and platelets from human embryonic stem cells (hESCs) on a large scal...
journal_title:Cell research
pub_type: 杂志文章
doi:10.1038/cr.2011.8
更新日期:2011-03-01 00:00:00
abstract::Dendritic cells (DCs) play a pivotal role in priming adaptive immunity. However, the involvement of DCs in controlling excessive and deleterious T cell responses remains poorly defined. Moreover, the metabolic dependence and regulation of DC function are unclear. Here we show that LKB1 signaling in DCs functions as a ...
journal_title:Cell research
pub_type: 杂志文章
doi:10.1038/s41422-019-0157-4
更新日期:2019-05-01 00:00:00
abstract::Transcriptional activator-like effectors (TALEs) have emerged as powerful tools for genome editing. A recent study published by Cell Research reports that fusion of thioredoxin to TALEs unlocks their full potential in live-cell imaging to accurately analyze genome instability, telomere attrition and epigenetic alterat...
journal_title:Cell research
pub_type: 评论,杂志文章
doi:10.1038/cr.2017.33
更新日期:2017-04-01 00:00:00
abstract::The muscle protein myosin binding protein C (MyBPC) is a large multi-domain protein whose role in the sarcomere is complex and not yet fully understood. Mutations in MyBPC are strongly associated with the heart disease familial hypertrophic cardiomyopathy (FHC) and these experiments of nature have provided some insigh...
journal_title:Cell research
pub_type: 杂志文章,评审
doi:10.1038/sj.cr.7290208
更新日期:2004-04-01 00:00:00
abstract::In searching for differentially expressed genes in human uterine leiomyomas (ULs), suppression subtractive hybridization was used to construct an UL up-regulated library, which turned out to represent 88 genes. After two rounds of screening by reverse Northern analysis, twenty genes were proved to be up-regulated, inc...
journal_title:Cell research
pub_type: 杂志文章
doi:10.1038/sj.cr.7290127
更新日期:2002-09-01 00:00:00
abstract::Hyaluronan binding protein 1 (HABP1) is a negatively charged multifunctional mammalian protein with a unique structural fold. Despite the fact that HABP1 possesses mitochondrial localization signal, it has also been localized to other cellular compartments. Using indirect immunofluorescence, we examined the sub-cellul...
journal_title:Cell research
pub_type: 杂志文章
doi:10.1038/sj.cr.7290284
更新日期:2005-03-01 00:00:00