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  • 1. Chen, J.
    et al.
    Yang, J.
    Sun, Xianqiang
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Theoretical Chemistry and Biology.
    Wang, Z.
    Cheng, X.
    Lu, W.
    Cai, X.
    Hu, C.
    Shen, X.
    Cao, P.
    Allosteric inhibitor remotely modulates the conformation of the orthestric pockets in mutant IDH2/R140Q2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, no 1, article id 16458Article in journal (Refereed)
    Abstract [en]

    Neomorphic mutation R140Q in the metabolic enzyme isocitrate dehydrogenase 2 (IDH2) is found to be a driver mutation in cancers. Recent studies revealed that allosteric inhibitors could selectively inhibit IDH2/R140Q and induce differentiation of TF-1 erythroleukemia and primary human AML cells. However, the allosteric inhibition mechanism is not very clear. Here, we report the results from computational studies that AGI-6780 binds tightly with the divalent cation binding helices at the homodimer interface and prevents the transition of IDH2/R140Q homodimer to a closed conformation that is required for catalysis, resulting in the decrease of the binding free energy of NADPHs. If the allosteric inhibitor is removed, the original open catalytic center of IDH2/R140Q will gradually reorganize to a quasi-closed conformation and the enzymatic activity might recover. Unlike IDH2/R140Q, AGI-6780 locks one monomer of the wild-type IDH2 in an inactive open conformation and the other in a half-closed conformation, which can be used to explain the selectivity of AGI-6780. Our results suggest that conformational changes are the primary contributors to the inhibitory potency of the allosteric inhibitor. Our study will also facilitate the understanding of the inhibitory and selective mechanisms of AG-221 (a promising allosteric inhibitor that has been approved by FDA) for mutant IDH2.

  • 2. Cheng, J.
    et al.
    Sun, Xianqiang
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Li, W.
    Liu, G.
    Tu, Yaoquan
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Tang, Y.
    Molecular switches of the κ opioid receptor triggered by 6′-GNTI and 5′-GNTI2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 18913Article in journal (Refereed)
    Abstract [en]

    The κ opioid receptor (κOR) is a member of G-protein-coupled receptors, and is considered as a promising drug target for treating neurological diseases. κOR selective 6′-GNTI was proved to be a G-protein biased agonist, whereas 5′-GNTI acts as an antagonist. To investigate the molecular mechanism of how these two ligands induce different behaviors of the receptor, we built two systems containing the 5′-GNTI-κOR complex and the 6′-GNTI-κOR complex, respectively, and performed molecular dynamics simulations of the two systems. We observe that transmembrane (TM) helix 6 of the κOR rotates about 4.6° on average in the κOR-6′-GNTI complex. Detailed analyses of the simulation results indicate that E2976.58 and I2946.55 play crucial roles in the rotation of TM6. In the simulation of the κOR-5′-GNTI system, it is revealed that 5′-GNTI can stabilize TM6 in the inactive state form. In addition, the kink of TM7 is stabilized by a hydrogen bond between S3247.47 and the residue V691.42 on TM1.

  • 3.
    Gao, Li
    et al.
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Sun, Xianqiang
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Tu, Yaoquan
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Ågren, Hans
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Eriksson, Leif A.
    Modification of the anticancer drug tamoxifen to avoid CYP2D6 polymorphism2013In: Canadian journal of chemistry (Print), ISSN 0008-4042, E-ISSN 1480-3291, Vol. 91, no 9, p. 916-924Article in journal (Refereed)
    Abstract [en]

    The prodrug tamoxifen (TAM) is the most widely used drug to treat breast cancer, and is metabolised to the active 4-hydroxy derivatives dominantly by hepatic CYP2D6. However, the application to patients with different polymorphic CYP2D6 has been under debate, because the efficacy of TAM is suspected to be suppressed in patients who have diminished CYP2D6 activity, resulting in inadequate active metabolites. We here propose modified structures, such as 4-methylTAM, which is highly possible to be activated by CYP3A, the most abundant CYP isoforms in the liver, whereby the genetic polymorphism of CYP2D6 is avoided. The diversity of CYP catalyzed metabolic paths for TAM and its derivatives are studied by quantum chemistry calculations on the reaction energies of the initial H atom abstraction steps. The ability of forming DNA adducts is compared through the formation enthalpy of the carbocation intermediate. The results suggest that the modified structures are safe with regard to forming DNA adducts and may be used as prodrugs in a wide range of patients, due to CYP3A, rather than CYP2D6, mediated activation.

  • 4.
    Sun, Xianqiang
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Theoretical Studies of G-Protein-Coupled Receptors2015Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The family of G-protein-coupled receptors (GPCRs) contains the largest number of drug targets in the human body, with more than a quarter of the clinically used drugs targeting them. Because of the important roles GPCRs play in the human body, the mechanisms of activation of GPCRs or ligands binding to GPCRs have captivated much research interest since the discovery of GPCRs. A number of GPCR crystal structures determined in recent years have provided us with unprecedented opportunities in investigating how GPCRs function through the conformational changes regulated by their ligands. This has motivated me to perform molecular dynamics (MD) simulations in combination with a variety of other modeling methods to study the activation of some GPCRs and their ligand selectivity.

    This thesis consists of six chapters. In the first chapter, a brief introduction of GPCRs and MD simulation techniques is given. Detailed MD simulation techniques, including pressure controlling methods and temperature coupling approaches, are described in chapter 2. The metadynamics simulation technique, used to enhance conformational sampling, is described in chapter 3. In chapter 4, I outline the inhomogeneous fluid theory used to calculate the thermodynamics properties of interfacial water molecules. Using the methods described in chapters 2-4, I carried out theoretical investigations on some GPCRs with the results summarized in chapter 5. In chapter 6, I provide a summary of the thesis with future work outlined in an outlook. 

  • 5.
    Sun, Xian-qiang
    et al.
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Chen, Lei
    Li, Yao-zong
    Li, Wei-hua
    Liu, Gui-xia
    Tu, Yao-quan
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Tang, Yun
    Structure-based ensemble-QSAR model: a novel approach to the study of the EGFR tyrosine kinase and its inhibitors2014In: Acta Pharmacologica Sinica, ISSN 1671-4083, E-ISSN 1745-7254, Vol. 35, no 2, p. 301-310Article in journal (Refereed)
    Abstract [en]

    Aim: To develop a novel 3D-QSAR approach for study of the epidermal growth factor receptor tyrosine kinase (EGFR TK) and its inhibitors. Methods: One hundred thirty nine EGFR TK inhibitors were classified into 3 clusters. Ensemble docking of these inhibitors with 19 EGFR TK crystal structures was performed. Three protein structures that showed the best recognition of each cluster were selected based on the docking results. Then, a novel QSAR (ensemble-QSAR) building method was developed based on the ligand conformations determined by the corresponding protein structures. Results: Compared with the 3D-QSAR model, in which the ligand conformations were determined by a single protein structure, ensemble-QSAR exhibited higher R2 (0.87) and Q2 (0.78) values and thus appeared to be a more reliable and better predictive model. Ensemble-QSAR was also able to more accurately describe the interactions between the target and the ligands. Conclusion: The novel ensemble-QSAR model built in this study outperforms the traditional 3D-QSAR model in rationality, and provides a good example of selecting suitable protein structures for docking prediction and for building structure-based QSAR using available protein structures.

  • 6.
    Sun, Xianqiang
    et al.
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Cheng, Jianxin
    Wang, Xu
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Tang, Yun
    Ågren, Hans
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Tu, Yaoquan
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Residues remote from the binding pocket control the antagonist selectivity towards the corticotropin-releasing factor receptor-12015In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, p. 8066-Article in journal (Refereed)
    Abstract [en]

    The corticotropin releasing factors receptor-1 and receptor-2 (CRF1R and CRF2R) are therapeutic targets for treating neurological diseases. Antagonists targeting CRF1R have been developed for the potential treatment of anxiety disorders and alcohol addiction. It has been found that antagonists targeting CRF1R always show high selectivity, although CRF1R and CRF2R share a very high rate of sequence identity. This has inspired us to study the origin of the selectivity of the antagonists. We have therefore built a homology model for CRF2R and carried out unbiased molecular dynamics and well-tempered metadynamics simulations for systems with the antagonist CP-376395 in CRF1R or CRF2R to address this issue. We found that the side chain of Tyr(6.63) forms a hydrogen bond with the residue remote from the binding pocket, which allows Tyr(6.63) to adopt different conformations in the two receptors and results in the presence or absence of a bottleneck controlling the antagonist binding to or dissociation from the receptors. The rotameric switch of the side chain of Tyr356(6.63) allows the breaking down of the bottleneck and is a perquisite for the dissociation of CP-376395 from CRF1R.

  • 7.
    Sun, Xianqiang
    et al.
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Laroch, Genevieve
    Wang, Xu
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Ågren, Hans
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Bowman, Gregory R.
    Giguõre, Patrick M.
    Tu, Yaoquan
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Propagation of the Allosteric Modulation Induced by Sodium in the delta-Opioid Receptor2017In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 23, no 19, p. 4615-4624Article in journal (Refereed)
    Abstract [en]

    Allosteric sodium in the helix bundle of a G protein-coupled receptor (GPCR) can modulate the receptor activation on the intracellular side. This phenomenon has confounded the GPCR community for decades. In this work, we present a theoretical model that reveals the mechanism of the allosteric modulation induced by sodium in the delta-opioid receptor. We found that the allosteric sodium ion exploits a distinct conformation of the key residue Trp2746.48 to propagate the modulation to helices 5 and 6, which further transmits along the helices and regulates their positions on the intracellular side. This mechanism is supported by subsequent functional assays. Remarkably, our results highlight the contrast between the allosteric effects towards two GPCR partners, the G protein and b-arrestin, as indicated by the fact that the allosteric modulation initiated by the sodium ion significantly affects the b-arrestin recruitment, while it alters the G protein signaling only moderately. We believe that the mechanism revealed in this work can be used to explain allosteric effects initiated by sodium in other GPCRs since the allosteric sodium is highly conserved across GPCRs. 

  • 8.
    Sun, Xianqiang
    et al.
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Ågren, Hans
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Tu, Yaoquan
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Computational investigation of G-proteins releasing from G-protein-coupled receptors2013In: Abstract of Papers of the American Chemical Society, ISSN 0065-7727, Vol. 246, p. 193-POLY-Article in journal (Other academic)
  • 9.
    Sun, Xianqiang
    et al.
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Ågren, Hans
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Tu, Yaoquan
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Function of the sodium ion in the activation of the δ-Opioid receptorManuscript (preprint) (Other academic)
  • 10.
    Sun, Xianqiang
    et al.
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Ågren, Hans
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Tu, Yaoquan
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Functional Water Molecules in Rhodopsin Activation2014In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 118, no 37, p. 10863-10873Article in journal (Refereed)
    Abstract [en]

    G-protein-coupled receptors (GPCRs) are integral membrane proteins that mediate cellular response to an extensive variety of extracellular stimuli. Studies of rhodopsin, a prototype GPCR, have suggested that water plays an important role in mediating the activation of family A GPCRs. However, our understanding of the function of water molecules in the GPCR activation is still rather limited because resolving the functional water molecules solely based on the results from existing experiments is challenging. Using all-atom molecular dynamics simulations in combination with inhomogeneous fluid theory, we identify in this work the positioning of functional water molecules in the inactive state, the Meta II state, and the constitutive active state of rhodopsin, basing on the thermodynamic signatures of the water molecules. We find that one hydration site likely functions as a switch to regulate the distance between Glu181 and the Schiff base in the rhodopsin activation. We observe that water molecules adjacent to the "NpxxY" motif are not as stable in the Meta II state as in the inactive state as indicated by the thermodynamics signatures, and we rationalize that the behaviors of these water molecules are closely correlated with the rearrangement of the water-mediated hydrogen-bond network in the "NPxxY" motif, which is essential for mediating the activation of the receptor. We thereby propose a hypothesis of the water-mediated rhodopsin activation pathway.

  • 11.
    Sun, Xianqiang
    et al.
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Ågren, Hans
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Tu, Yaoquan
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Microsecond Molecular Dynamics Simulations Provide Insight into the Allosteric Mechanism of the Gs Protein Uncoupling from the beta(2) Adrenergic Receptor2014In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 118, no 51, p. 14737-14744Article in journal (Refereed)
    Abstract [en]

    Experiments have revealed that in the beta(2) adrenergic receptor (beta(2)AR)-Gs protein complex the a subunit (G alpha s) of the Gs protein can adopt either an open conformation or a closed conformation. In the open conformation the Gs protein prefers to bind to the beta(2)AR, while in the closed conformation an uncoupling of the Gs protein from the beta(2)AR occurs. However, the mechanism that leads to such different behaviors of the Gs protein remains unclear. Here, we report results from microsecond molecular dynamics simulations and community network analysis of the beta(2)AR-Gs complex with G alpha s in the open and closed conformations. We observed that the complex is stabilized differently in the open and closed conformations. The community network analysis reveals that in the closed conformation there exists strong allosteric communication between the beta(2)AR and G beta gamma, mediated by G alpha s. We suggest that such high information flows are necessary for the Gs protein uncoupling from the beta(2)AR.

  • 12.
    Wang, Xu
    et al.
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Granata, Daniele
    Sun, Xianqiang
    Wang, Yong
    Ågren, Hans
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Tu, Yaoquan
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Coupled Folding and Binding of the Intrinsically Disordered AICD Peptide in the Presence of the Fe65-PTB2 ProteinArticle in journal (Refereed)
    Abstract [en]

    Intrinsically disordered proteins (IDPs) exert important cellular functions. Many IDPs that are partially or completely disordered in free states fold into well-defined tertiary structures upon binding to their targets, an association process involving coupled folding and binding. Although many biophysical and computational approaches have been applied to study coupled folding and binding reactions over the past decade, an atomic-level description of the binding of IDPs and the underlying mechanisms still represents a major challenge. Here, we present results of atomistic simulations of a natively unfolded peptide AICD binding to its target Fe65-PTB2. By bias-exchange metadynamics we computed a three-dimensional free-energy landscape for the binding process and identified several local minima corresponding to distinct intermediate states. The associated free energy is in good agreement with experimental results. By kinetic Monte Carlo simulations, we obtained two possible paths for AICD binding to Fe65-PTB2 that both confirm that the identified intermediates are on-path. We described the binding process with atomistic details, and found that the partially folded AICD peptide first approaches the Fe65-PTB2 protein to form different diffusion encounter complexes, which then evolve through multiple intermediates to the final native state. The binding of AICD proceeds via a kinetic divide-and-conquer strategy by which AICD folds in a stepwise fashion. We propose that the interaction of AICD with the target takes place via an induced fit mechanism. 

  • 13.
    Wang, Xu
    et al.
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Sun, Xianqiang
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Kuang, Guanglin
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Ågren, Hans
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Tu, Yaoquan
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    A theoretical study on the molecular determinants of the affibody protein ZAbeta3 bound to an amyloid beta peptide.2015In: Physical Chemistry, Chemical Physics - PCCP, ISSN 1463-9076, E-ISSN 1463-9084, Vol. 17, no 26, p. 16886-16893Article in journal (Refereed)
    Abstract [en]

    Amyloid beta (A beta) peptides are small cleavage products of the amyloid precursor protein. Aggregates of A beta peptides are thought to be linked with Alzheimer's and other neurodegenerative diseases. Strategies aimed at inhibiting amyloid formation and promoting A beta clearance have been proposed and investigated in in vitro experiments and in vivo therapies. A recent study indicated that a novel affibody protein Z(A beta 3), which binds to an A beta 40 monomer with a binding affinity of 17 nM, is able to prevent the aggregation of A beta 40. However, little is known about the energetic contribution of each residue in Z(A beta 3) to the formation of the (Z(A beta 3))(2):A beta complex. To address this issue, we carried out unbiased molecular dynamics simulations and molecular mechanics Poisson-Boltzmann surface area calculations. Through the per-residue decomposition scheme, we identified that the van der Waals interactions between the hydrophobic residues of (Z(A beta 3))(2) and those at the exterior and interior faces of A beta are the main contributors to the binding of (Z(A beta 3))(2) to A beta. Computational alanine scanning identified 5 hot spots, all residing in the binding interface and contributing to the binding of (Z(A beta 3))(2) to A beta through the hydrophobic effect. In addition, the amide hydrogen bonds in the 4-strand beta-sheet and the pi-pi stacking were also analyzed. Overall, our study provides a theoretical basis for future experimental improvement of the Z(A beta 3) peptide binding to A beta.

  • 14. Xu, Fang
    et al.
    Chen, Hong
    Xu, Jingyi
    Liang, Xue
    He, Xuelan
    Shao, Binhao
    Sun, Xianqiang
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Li, Bing
    Deng, Xiaoliang
    Yuan, Mu
    Synthesis, structure-activity relationship and biological evaluation of novel arylpiperzines as alpha(1A/1D)-AR subselective antagonists for BPH2015In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 23, no 24, p. 7735-7742Article in journal (Refereed)
    Abstract [en]

    A series of novel arylpiperazine derivatives as alpha(1A/1D)-adrenergic receptors (AR) subtype selective antagonists were designed, synthesized and evaluated for their antagonistic activities towards alpha(1)-ARs (alpha(1A), alpha(1B), and alpha(1D)). Compounds 9, 12, 13, 15, 17, 18, 21, 22, 25 and 26 exerted strong antagonistic effects on alpha(1A) and/or alpha(1D) subtypes over alpha(1B) in vitro. SAR analysis indicated that chloride at the ortho-phenyl position for compound 17 was beneficial for the highest alpha(1A/D)-AR sub-selectivity. Moreover, molecular docking study of compound 17 with the homology-modeled alpha(1)-ARs (alpha(1A), alpha(1B), and alpha(1D)) structures exhibited differences of key amino resides in the docking pocket which may influence the subtype selectivity. ILE 193 of alpha(1A) was validated as the key residues for binding ligand. This work provides useful information for finding more new potential drugs in clinic in treating benign prostatic hyperplasia (BPH).

  • 15. Zhang, Jingwei
    et al.
    Sun, Yuan
    Wang, Yaoyao
    Lu, Meng
    He, Jichao
    Liu, Jiali
    Chen, Qianying
    Zhang, Xiaoxuan
    Zhou, Fang
    Wang, Guangji
    Sun, Xianqiang
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Non-antibiotic agent ginsenoside 20(S)-Rh2 enhanced the antibacterial effects of ciprofloxacin in vitro and in vivo as a potential NorA inhibitor2014In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 740, p. 277-284Article in journal (Refereed)
    Abstract [en]

    The aim of this study is to explore the potential enhancing effect of ginsenoside 20(s)-Rh2 (Rh2) towards ciprofloxacin (CIP) against Staphylococcus aureus (S. aureus) infection in vitro and in vivo, and analyze the possible mechanisms through NorA inhibition from a target cellular pharmacokinetic view. In combination with non-toxic dosage of Rh2, the susceptibilities of S. (wrens strains to CIP were significantly augmented, and the antibacterial kinetics of CIP in the S. aurora strains were markedly promoted. This enhancing effect of Rh2 towards CIP was also observed in S. aureus infected peritonitis mice, with elevated survival rate and reduced bacteria counts in blood. However, Rh2 did not influence the plasma concentrations of OP. Further analysis indicated that Rh2 significantly promoted the accumulations of ClP in S. aureus, and inhibited the NorA mediated efflux of pyronin Y. The expressions of NorA gene on S. aureus were positively correlated with the enhancing effect of Rh2 with OP. This is the first report of the enhancing effect of Rh2 with ClP for S. aureits infection in vitro and in vivo, of which it is probably that Rh2 inhibited NorA-mediaLed efflux and promoted the accumulation of ClP in the bacteria.

  • 16. Zhang, Juan
    et al.
    Gu, Shikai
    Sun, Xianqiang
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Li, Weihua
    Tang, Yun
    Liu, Guixia
    Computational insight into conformational states of glucagon-like peptide-1 receptor (GLP-1R) and its binding mode with GLP-12016In: RSC Advances, ISSN 2046-2069, E-ISSN 2046-2069, Vol. 6, no 16, p. 13490-13497Article in journal (Refereed)
    Abstract [en]

    The glucagon-like peptide-1 receptor (GLP-1R) has captivated researchers because of its tremendous therapeutic effects for the treatment of type 2 diabetes mellitus (T2DM). However, since the full-length crystal structure of GLP-1R has not been revealed yet, the molecular binding mode and the activation mechanism remain unclear, which will be the obstacle for the discovery of novel potent GLP-1R agonists. In the present study, we constructed the model of GLP-1R in its full length and explored the binding modes between GLP-1 and GLP-1R by means of a bunch of computational methods including homology modeling, protein-protein docking, and molecular dynamics simulations. Our model is in agreement with previous experiment and the results from our MD simulations that verified the binding modes between GLP-1 and GLP-1R are reasonable. What's more, we found the absence or presence of GLP-1 significantly affected the conformation of extracellular domain (ECD) of GLP-1R. The GLP-1R in the apo form stabilized in a 'closed' state which is unfavorable to the binding of GLP-1, resembling as the GCGR. By contrast, in the GLP-1/GLP-1R complex, GLP-1R maintained an 'open' state.

1 - 16 of 16
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