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Publications (10 of 14) Show all publications
Chen, J., Yang, J., Sun, X., Wang, Z., Cheng, X., Lu, W., . . . Cao, P. (2017). Allosteric inhibitor remotely modulates the conformation of the orthestric pockets in mutant IDH2/R140Q. Scientific Reports, 7(1), Article ID 16458.
Open this publication in new window or tab >>Allosteric inhibitor remotely modulates the conformation of the orthestric pockets in mutant IDH2/R140Q
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2017 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, no 1, article id 16458Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Nature Publishing Group, 2017
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:kth:diva-227115 (URN)10.1038/s41598-017-16427-w (DOI)000416398100008 ()2-s2.0-85036511176 (Scopus ID)
Note

QC 20180508

Available from: 2018-05-08 Created: 2018-05-08 Last updated: 2019-10-18Bibliographically approved
Zhang, J., Gu, S., Sun, X., Li, W., Tang, Y. & Liu, G. (2016). Computational insight into conformational states of glucagon-like peptide-1 receptor (GLP-1R) and its binding mode with GLP-1. RSC Advances, 6(16), 13490-13497
Open this publication in new window or tab >>Computational insight into conformational states of glucagon-like peptide-1 receptor (GLP-1R) and its binding mode with GLP-1
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2016 (English)In: RSC Advances, ISSN 2046-2069, E-ISSN 2046-2069, Vol. 6, no 16, p. 13490-13497Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2016
National Category
Chemical Sciences
Identifiers
urn:nbn:se:kth:diva-183222 (URN)10.1039/c5ra26102c (DOI)000369546100088 ()2-s2.0-84956921127 (Scopus ID)
Note

QC 20160303

Available from: 2016-03-03 Created: 2016-03-03 Last updated: 2017-11-30Bibliographically approved
Cheng, J., Sun, X., Li, W., Liu, G., Tu, Y. & Tang, Y. (2016). Molecular switches of the κ opioid receptor triggered by 6′-GNTI and 5′-GNTI. Scientific Reports, 6, Article ID 18913.
Open this publication in new window or tab >>Molecular switches of the κ opioid receptor triggered by 6′-GNTI and 5′-GNTI
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2016 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 18913Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Nature Publishing Group, 2016
National Category
Biophysics
Identifiers
urn:nbn:se:kth:diva-181442 (URN)10.1038/srep18913 (DOI)000368677900001 ()26742690 (PubMedID)2-s2.0-84953897601 (Scopus ID)
Funder
Swedish National Infrastructure for Computing (SNIC), SNIC2014-11-31Swedish National Infrastructure for Computing (SNIC), SNIC2014-1-326
Note

QC 20160204. QC 20160218

Available from: 2016-02-04 Created: 2016-02-02 Last updated: 2017-11-30Bibliographically approved
Wang, X., Sun, X., Kuang, G., Ågren, H. & Tu, Y. (2015). A theoretical study on the molecular determinants of the affibody protein ZAbeta3 bound to an amyloid beta peptide.. Physical Chemistry, Chemical Physics - PCCP, 17(26), 16886-16893
Open this publication in new window or tab >>A theoretical study on the molecular determinants of the affibody protein ZAbeta3 bound to an amyloid beta peptide.
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2015 (English)In: Physical Chemistry, Chemical Physics - PCCP, ISSN 1463-9076, E-ISSN 1463-9084, Vol. 17, no 26, p. 16886-16893Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Royal Society of Chemistry, 2015
National Category
Physical Chemistry
Identifiers
urn:nbn:se:kth:diva-170676 (URN)10.1039/c5cp00615e (DOI)000356874000028 ()26060853 (PubMedID)2-s2.0-84934344084 (Scopus ID)
Funder
Swedish Foundation for Strategic Research , SSF RB13-0192
Note

QC 20150707

Available from: 2015-07-07 Created: 2015-07-03 Last updated: 2017-12-04Bibliographically approved
Sun, X., Cheng, J., Wang, X., Tang, Y., Ågren, H. & Tu, Y. (2015). Residues remote from the binding pocket control the antagonist selectivity towards the corticotropin-releasing factor receptor-1. Scientific Reports, 5, 8066
Open this publication in new window or tab >>Residues remote from the binding pocket control the antagonist selectivity towards the corticotropin-releasing factor receptor-1
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2015 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, p. 8066-Article in journal (Refereed) Published
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.

Keywords
Protein-Coupled Receptors, Beta(2)-Adrenergic Receptor, Molecular-Dynamics, Conformations, Pharmacology, Sensitivity, Activation, Kinetics, Pathway
National Category
Biological Sciences Chemical Sciences
Identifiers
urn:nbn:se:kth:diva-160743 (URN)10.1038/srep08066 (DOI)000348435800001 ()25628267 (PubMedID)
Funder
Swedish National Infrastructure for Computing (SNIC), SNIC2013-26-31 SNIC2013-1-236
Note

QC 20150302

Available from: 2015-03-02 Created: 2015-02-27 Last updated: 2017-12-04Bibliographically approved
Xu, F., Chen, H., Xu, J., Liang, X., He, X., Shao, B., . . . Yuan, M. (2015). Synthesis, structure-activity relationship and biological evaluation of novel arylpiperzines as alpha(1A/1D)-AR subselective antagonists for BPH. Bioorganic & Medicinal Chemistry, 23(24), 7735-7742
Open this publication in new window or tab >>Synthesis, structure-activity relationship and biological evaluation of novel arylpiperzines as alpha(1A/1D)-AR subselective antagonists for BPH
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2015 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 23, no 24, p. 7735-7742Article in journal (Refereed) Published
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).

Place, publisher, year, edition, pages
Elsevier, 2015
Keywords
alpha(1)-ARs, Subtype selectivity, Arylpiperazine derivatives, Antagonic activity, Homology modeling, Structure-activity relationship
National Category
Biochemistry and Molecular Biology Chemical Sciences
Identifiers
urn:nbn:se:kth:diva-180493 (URN)10.1016/j.bmc.2015.11.020 (DOI)000366645600023 ()2-s2.0-84949723621 (Scopus ID)
Note

QC 20160119

Available from: 2016-01-19 Created: 2016-01-14 Last updated: 2017-11-30Bibliographically approved
Sun, X. (2015). Theoretical Studies of G-Protein-Coupled Receptors. (Doctoral dissertation). Stockholm: KTH Royal Institute of Technology
Open this publication in new window or tab >>Theoretical Studies of G-Protein-Coupled Receptors
2015 (English)Doctoral 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. 

Place, publisher, year, edition, pages
Stockholm: KTH Royal Institute of Technology, 2015. p. viii, 60
Series
TRITA-BIO-Report, ISSN 1654-2312 ; 2015:13
National Category
Biological Sciences
Research subject
Biological Physics
Identifiers
urn:nbn:se:kth:diva-166407 (URN)978-91-7595-589-6 (ISBN)
Public defence
2015-06-03, FD5 AlbaNova, Roslagstullsbacken, KTH, Stockholm, 10:00 (English)
Opponent
Supervisors
Note

QC 201505020

Available from: 2015-05-08 Created: 2015-05-08 Last updated: 2015-05-20Bibliographically approved
Sun, X., Ågren, H. & Tu, Y. (2014). Functional Water Molecules in Rhodopsin Activation. Journal of Physical Chemistry B, 118(37), 10863-10873
Open this publication in new window or tab >>Functional Water Molecules in Rhodopsin Activation
2014 (English)In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 118, no 37, p. 10863-10873Article in journal (Refereed) Published
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.

Keywords
Protein-Coupled-Receptors, Ligand-Binding, Metarhodopsin-Ii, Squid Rhodopsin, Dynamics, Light, Thermodynamics, Chromophore, Photoactivation, Crystallography
National Category
Physical Chemistry
Identifiers
urn:nbn:se:kth:diva-154376 (URN)10.1021/jp505180t (DOI)000342120100006 ()2-s2.0-84926443535 (Scopus ID)
Note

QC 20141021

Available from: 2014-10-21 Created: 2014-10-20 Last updated: 2017-12-05Bibliographically approved
Sun, X., Ågren, H. & Tu, Y. (2014). Microsecond Molecular Dynamics Simulations Provide Insight into the Allosteric Mechanism of the Gs Protein Uncoupling from the beta(2) Adrenergic Receptor. Journal of Physical Chemistry B, 118(51), 14737-14744
Open this publication in new window or tab >>Microsecond Molecular Dynamics Simulations Provide Insight into the Allosteric Mechanism of the Gs Protein Uncoupling from the beta(2) Adrenergic Receptor
2014 (English)In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 118, no 51, p. 14737-14744Article in journal (Refereed) Published
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.

Keywords
Coupled Receptors, Crystal-Structure, Structural Basis, Activation Mechanism, Nobel Lecture, Networks, Complex, Mode, Agonists
National Category
Chemical Sciences
Identifiers
urn:nbn:se:kth:diva-159623 (URN)10.1021/jp506579a (DOI)000347360100002 ()2-s2.0-84919933719 (Scopus ID)
Funder
Swedish National Infrastructure for Computing (SNIC), SNIC025/12-38
Note

QC 20150209

Available from: 2015-02-09 Created: 2015-02-05 Last updated: 2017-12-04Bibliographically approved
Zhang, J., Sun, Y., Wang, Y., Lu, M., He, J., Liu, J., . . . Sun, X. (2014). Non-antibiotic agent ginsenoside 20(S)-Rh2 enhanced the antibacterial effects of ciprofloxacin in vitro and in vivo as a potential NorA inhibitor. European Journal of Pharmacology, 740, 277-284
Open this publication in new window or tab >>Non-antibiotic agent ginsenoside 20(S)-Rh2 enhanced the antibacterial effects of ciprofloxacin in vitro and in vivo as a potential NorA inhibitor
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2014 (English)In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 740, p. 277-284Article in journal (Refereed) Published
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.

Keywords
Ginsenoside 20(S)-Rh2, Bacteria resistance, Ciprofloxacin, Staphylococcus aureus, NorA efflux pump
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:kth:diva-153242 (URN)10.1016/j.ejphar.2014.07.020 (DOI)000341163700035 ()2-s2.0-84905496176 (Scopus ID)
Note

QC 20141016

Available from: 2014-10-16 Created: 2014-10-03 Last updated: 2018-01-11Bibliographically approved
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ORCID iD: ORCID iD iconorcid.org/0000-0001-9035-7086

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