Publications by authors named "Li-Nan Chen"

6 Publications

  • Page 1 of 1

Molecular insights into ago-allosteric modulation of the human glucagon-like peptide-1 receptor.

Nat Commun 2021 06 18;12(1):3763. Epub 2021 Jun 18.

School of Pharmacy, Fudan University, Shanghai, China.

The glucagon-like peptide-1 (GLP-1) receptor is a validated drug target for metabolic disorders. Ago-allosteric modulators are capable of acting both as agonists on their own and as efficacy enhancers of orthosteric ligands. However, the molecular details of ago-allosterism remain elusive. Here, we report three cryo-electron microscopy structures of GLP-1R bound to (i) compound 2 (an ago-allosteric modulator); (ii) compound 2 and GLP-1; and (iii) compound 2 and LY3502970 (a small molecule agonist), all in complex with heterotrimeric G. The structures reveal that compound 2 is covalently bonded to C347 at the cytoplasmic end of TM6 and triggers its outward movement in cooperation with the ECD whose N terminus penetrates into the GLP-1 binding site. This allows compound 2 to execute positive allosteric modulation through enhancement of both agonist binding and G protein coupling. Our findings offer insights into the structural basis of ago-allosterism at GLP-1R and may aid the design of better therapeutics.
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http://dx.doi.org/10.1038/s41467-021-24058-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213797PMC
June 2021

[Effects of different nitrogen application rates on dry matter accumulation, distribution and yield of grape under alternate partial root-zone drip irrigation.]

Ying Yong Sheng Tai Xue Bao 2021 May;32(5):1807-1815

School of Life Science, Taizhou University, Taizhou 318000, Zhejiang, China.

To get an optimal mode of irrigation and nitrogen supply for table grape production in North China, a pot experiment was conducted to investigate the effects of different irrigation modes and N application rates on dry matter accumulation and distribution, yield, water use efficiency, and nitrogen use efficiency of table grape. The irrigation modes included conventional drip irrigation (CDI, with sufficient irrigation), alternate partial root-zone drip irrigation (ADI, with 50% amount of the irrigation water of CDI) and fixed partial root-zone drip irrigation (FDI, with 50% amount of the irrigation water of CDI). The nitrogen application rates were set at 0.4 (N), 0.8 (N) and 1.2 (N) g·kg dry soil. The results showed that compared with CDI, ADI and FDI reduced new shoot pruning amount by 34.8% and 11.2%, respectively. New shoot pruning amount increased with increasing N application rates, being highest under CDIN. Dry matter accumulation of ADI was the highest, being 5.1% and 12.8% higher than CDI and FDI. Dry matter accumulation was higher under N and N than N. Compared with CDI and FDI, leaf to fruit ratio reduced but harvest index significantly increased in ADI, while those variables showed no significant difference among diffe-rent N application rates. The ratio of pruning amount to the biomass accumulated in the current year in ADIN was the lowest among the treatments. Compared with CDI and FDI, ADI increased grape fruit yield by 6.0% and 10.4%, respectively. Fruit yield was enhanced with increasing nitrogen application rates under the same irrigation condition, with the highest yield under the ADIN and ADIN. Water use efficiency (WUE) increased significantly in ADI compared with CDI and FDI, with the highest value being observed in ADI coupled with N or N. Nitrogen use efficiency (NUE) showed a trend of ADI>CDI>FDI. In addition, NUE decreased with increasing nitrogen supply level across the irrigation modes. In conclusion, ADIN could reduce the redundant growth of grape tree, promote the transfer of dry matter to fruit, which increased yield and use efficiency of both water and nitrogen, which is a suitable coupling water and nitrogen supply mode for grape production in northern China.
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http://dx.doi.org/10.13287/j.1001-9332.202105.023DOI Listing
May 2021

A unique hormonal recognition feature of the human glucagon-like peptide-2 receptor.

Cell Res 2020 12 25;30(12):1098-1108. Epub 2020 Nov 25.

The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.

Glucagon-like peptides (GLP-1 and GLP-2) are two proglucagon-derived intestinal hormones that mediate distinct physiological functions through two related receptors (GLP-1R and GLP-2R) which are important drug targets for metabolic disorders and Crohn's disease, respectively. Despite great progress in GLP-1R structure determination, our understanding on the differences of peptide binding and signal transduction between these two receptors remains elusive. Here we report the electron microscopy structure of the human GLP-2R in complex with GLP-2 and a G heterotrimer. To accommodate GLP-2 rather than GLP-1, GLP-2R fine-tunes the conformations of the extracellular parts of transmembrane helices (TMs) 1, 5, 7 and extracellular loop 1 (ECL1). In contrast to GLP-1, the N-terminal histidine of GLP-2 penetrates into the receptor core with a unique orientation. The middle region of GLP-2 engages with TM1 and TM7 more extensively than with ECL2, and the GLP-2 C-terminus closely attaches to ECL1, which is the most protruded among 9 class B G protein-coupled receptors (GPCRs). Functional studies revealed that the above three segments of GLP-2 are essential for GLP-2 recognition and receptor activation, especially the middle region. These results provide new insights into the molecular basis of ligand specificity in class B GPCRs and may facilitate the development of more specific therapeutics.
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http://dx.doi.org/10.1038/s41422-020-00442-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785020PMC
December 2020

Cryo-EM structures of inactive and active GABA receptor.

Cell Res 2020 07 3;30(7):564-573. Epub 2020 Jun 3.

Department of Biophysics, and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, Zhejiang, China.

Metabotropic GABA G protein-coupled receptor functions as a mandatory heterodimer of GB1 and GB2 subunits and mediates inhibitory neurotransmission in the central nervous system. Each subunit is composed of the extracellular Venus flytrap (VFT) domain and transmembrane (TM) domain. Here we present cryo-EM structures of full-length human heterodimeric GABA receptor in the antagonist-bound inactive state and in the active state complexed with an agonist and a positive allosteric modulator in the presence of G protein at a resolution range of 2.8-3.0 Å. Our structures reveal that agonist binding stabilizes the closure of GB1 VFT, which in turn triggers a rearrangement of TM interfaces between the two subunits from TM3-TM5/TM3-TM5 in the inactive state to TM6/TM6 in the active state and finally induces the opening of intracellular loop 3 and synergistic shifting of TM3, 4 and 5 helices in GB2 TM domain to accommodate the α5-helix of G. We also observed that the positive allosteric modulator anchors at the dimeric interface of TM domains. These results provide a structural framework for understanding class C GPCR activation and a rational template for allosteric modulator design targeting the dimeric interface of GABA receptor.
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http://dx.doi.org/10.1038/s41422-020-0350-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7343782PMC
July 2020

Dysregulated renin-angiotensin system contributes to acute lung injury caused by hind-limb ischemia-reperfusion in mice.

Shock 2013 Nov;40(5):420-9

*Department of Physiology, School of Basic Medical Science, and †International Education College, Hebei United University, Tangshan, People's Republic of China.

The mechanism of acute lung injury (ALI) following limb ischemia-reperfusion (LIR) is not yet clear. We speculate that the unbalanced expression of angiotensin-converting enzymes (ACE and ACE2) and angiotensins [Ang II and Ang-(1-7)] in the renin-angiotensin system (RAS) is a major cause of ALI. To prove this hypothesis, pathological changes, lung edema, and permeability of wild-type mice at different time points within 12 h of reperfusion after 2 h of hind-limb ischemia were first detected by morphological method, measurements of wet-to-dry weight ratio, and bronchoalveolar lavage fluid. Meanwhile, the changes of lung ACE/ACE2 mRNA and protein expression were surveyed by the methods of real-time reverse transcription-polymerase chain reaction, Western blotting, and immunohistochemistry. Angiotensin II/Ang-(1-7) levels in the blood serum and lung tissue were measured by enzyme-linked immunosorbent assay. Then the effects of ACE2 gene insertion and deletion on the previously mentioned parameters were investigated in the mice being exposed to hind-limb 2-h ischemia and 4-h reperfusion. The results revealed that lung injuries in the wild-type mice were gradually aggravated, and the expression of ACE in lung tissue was progressively increased, whereas that of ACE2 decreased within 12 h after LIR. Unexpectedly, both Ang II and Ang-(1-7) in the lung tissue were obviously increased after LIR, showing Ang-(1-7) higher than Ang II in the early stage of reperfusion but lower than Ang II at the late stage of reperfusion. Unlike local Ang II/Ang-(1-7) changes, circulating Ang-(1-7) became greatly descending, and Ang II was markedly ascending from the start of reperfusion, corresponding to local ACE/ACE2 unbalanced expression. ACE2 transgenosis improved the imbalance of ACE/ACE2 and Ang II/Ang-(1-7) expression and alleviated lung injuries, whereas ACE2 knockout further aggravated the imbalance of ACE/ACE2 and Ang II/Ang-(1-7) expression and made lung injuries more serious in the post-LIR mice. The results indicate that the dysregulation of local and circulating RAS with increased expression of ACE/Ang II and decreased expression of ACE2/Ang-(1-7) contribute to ALI caused by LIR in mice. Maintaining RAS homeostasis through upregulating ACE2 expression may lessen lung injury, which provides a new idea for the treatment of posttraumatic ALI.
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http://dx.doi.org/10.1097/SHK.0b013e3182a6953eDOI Listing
November 2013

[Local renin-angiotensin system disequilibrium and acute lung injury].

Sheng Li Ke Xue Jin Zhan 2013 Apr;44(2):133-7

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April 2013
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