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Dive into the research topics where Shanshan Guan is active.

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Featured researches published by Shanshan Guan.


Journal of Biomolecular Structure & Dynamics | 2016

Insight into the interactive residues between two domains of human somatic Angiotensin-converting enzyme and Angiotensin II by MM-PBSA calculation and steered molecular dynamics simulation

Shanshan Guan; Weiwei Han; Hao Zhang; Song Wang; Yaming Shan

Angiotensin-converting enzyme (ACE), a membrane-bound zinc metallopeptidase, catalyzes the formation of Angiotensin-II (AngII) and the deactivation of bradykinin in the renin–angiotensin-aldosterone and kallikrein–kinin systems. As a hydrolysis product of ACE, AngII is regarded as an inhibitor and displays stronger competitive inhibition in the C-domain than the N-domain of ACE. However, the AngII binding differences between the two domains and the mechanisms behind AngII dissociation from the C-domain are rarely explored. In this work, molecular docking, Molecular Mechanics/Poisson–Boltzmann Surface Area calculation, and steered molecular dynamics (SMD) are applied to explore the structures and interactions in the binding or unbinding of AngII with the two domains of human somatic ACE. Calculated free energy values suggest that the C-domain–AngII complex is more stable than the N-domain–AngII complex, consistent with available experimental data. SMD simulation results imply that electrostatic interaction is dominant in the dissociation of AngII from the C-domain. Moreover, Gln106, Asp121, Glu123, and Tyr213 may be the key residues in the unbinding pathway of AngII. The simulation results in our work provide insights into the interactions between the two domains of ACE and its natural peptide inhibitor AngII at a molecular level. Moreover, the results provide theoretical clues for the design of new inhibitors.


Journal of Chemical Information and Modeling | 2016

Structural Basis of Fullerene Derivatives as Novel Potent Inhibitors of Protein Tyrosine Phosphatase 1B: Insight into the Inhibitory Mechanism through Molecular Modeling Studies

Mengdan Qian; Yaming Shan; Shanshan Guan; Hao Zhang; Song Wang; Wei‐wei Han

Protein tyrosine phosphatase 1B (PTP1B) has become an outstanding target for the treatment of diabetes and obesity. Recent research has demonstrated that some fullerene derivatives serve as a new nanoscale-class of potent inhibitors of PTP1B, but the specific mechanism remains unclear. Several molecular modeling methods (molecular docking, molecular dynamics simulations, and molecular mechanics/generalized Born surface area calculations) were integrated to provide insight into the binding mode and inhibitory mechanism of the new class of fullerene inhibitors. The results reveal that PTP1B with an open WPD loop is more susceptible to the combination with the fullerene inhibitor because of their comparable shapes and sizes. When the WPD loop fluctuates to the open conformation, the inhibitor falls into the active pocket and induces conformational rotation of the WPD loop. This rotation is closely related to the reduction of the catalytic activity of PTP1B. In addition, it is suggested that compound 1, like compound 2, is a competitive inhibitor since it blocks the active site to prevent the binding of the substrate. The high binding affinity of fullerene-based compounds and the transition of the WPD loop, caused by the specific structural property of the hydrophobic fullerene core and the appended polar groups, make these fullerene derivatives efficient competitive inhibitors. The theoretical results provide useful clues for further investigation of the noval inhibitors of PTP1B at the nanoscale.


Emerging microbes & infections | 2016

Evaluation of the immunogenicity and protective effects of a trivalent chimeric norovirus P particle immunogen displaying influenza HA2 from subtypes H1, H3 and B

Xin Gong; He Yin; Yuhua Shi; Xiaoqiu He; Yongjiao Yu; Shanshan Guan; Ziyu Kuai; Nasteha M Haji; Nafisa M Haji; Wei Kong; Yaming Shan

The ectodomain of the influenza A virus (IAV) hemagglutinin (HA) stem is highly conserved across strains and has shown promise as a universal influenza vaccine in a mouse model. In this study, potential B-cell epitopes were found through sequence alignment and epitope prediction in a stem fragment, HA2:90-105, which is highly conserved among virus subtypes H1, H3 and B. A norovirus (NoV) P particle platform was used to express the HA2:90-105 sequences from subtypes H1, H3 and B in loops 1, 2 and 3 of the protrusion (P) domain, respectively. Through mouse immunization and microneutralization assays, the immunogenicity and protective efficacy of the chimeric NoV P particle (trivalent HA2-PP) were tested against infection with three subtypes (H1N1, H3N2 and B) of IAV in Madin–Darby canine kidney cells. The protective efficacy of the trivalent HA2-PP was also evaluated preliminarily in vivo by virus challenge in the mouse model. The trivalent HA2-PP immunogen induced significant IgG antibody responses, which could be enhanced by a virus booster vaccination. Moreover, the trivalent HA2-PP immunogen also demonstrated in vitro neutralization of the H3 and B viruses, and in vivo protection against the H3 virus. Our results support the notion that a broadly protective vaccine approach using an HA2-based NoV P particle platform can provide cross-protection against challenge viruses of different IAV subtypes. The efficacy of the immunogen should be further enhanced for practicality, and a better understanding of the protective immune mechanism will be critical for the development of HA2-based multivalent vaccines.


Journal of Structural Biology | 2016

Structural and molecular basis of cellulase Cel48F by computational modeling: Insight into catalytic and product release mechanism.

Mengdan Qian; Shanshan Guan; Yaming Shan; Hao Zhang; Song Wang

As a processive cellulase, Cel48F from Clostridium cellulolyticum plays a crucial role in cellulose fiber degradation. It has been confirmed in experiment that residue Glu44 will greatly affect the catalytic activity but the mechanism is still unknown. In this study, conventional molecular dynamics, steered molecular dynamics and free energy calculation were integrated to simulate the hydrolysis and product release process to gain insights into the factors that influence catalytic activity. Analysis of simulation results indicated that Glu44 could maintain the proper conformation of its substrate to ensure successful cleavage reaction or serve as a base required in the inverting mechanism in hydrolysis. After hydrolysis is completed, residues Glu44, Asp494, Trp611 and Glu55 participate in hydrogen bond rearrangement during product releasing process. This rearrangement can reduce the sliding barrier and stimulate the product to move toward the exit in the initial release stage. Dependent on the rearrangement, the product moves toward the exit and is exposed to an increasing amount of solvent molecules, which makes solvent effect more and more notable. With the assistance of solvent interaction, product can get rid of the enzyme more easily. However, the subsequent release process remains uncertain because of the disordered motion of solvent molecules. This work provides theoretical data as a basis of cellulase modification or mutation.


Immunology Letters | 2016

Conserved stem fragment from H3 influenza hemagglutinin elicits cross-clade neutralizing antibodies through stalk-targeted blocking of conformational change during membrane fusion

Xin Gong; He Yin; Yuhua Shi; Shanshan Guan; Xiaoqiu He; Lan Yang; Yongjiao Yu; Ziyu Kuai; Chunlai Jiang; Wei Kong; Song Wang; Yaming Shan

Currently available influenza vaccines typically fail to elicit/boost broadly neutralizing antibodies due to the mutability of virus sequences and conformational changes during protective immunity, thereby limiting their efficacy. This problem needs to be addressed by further understanding the mechanisms of neutralization and finding the desired neutralizing site during membrane fusion. This study specifically focused on viruses of the H3N2 subtype, which have persisted as a principal source of influenza-related morbidity and mortality in humans since the 1968 influenza pandemic. Through sequence alignment and epitope prediction, a series of highly conserved stem fragments (spanning 47 years) were found and coupled to the Keyhole Limpet Hemocyanin (KLH) protein. By application of a combinatorial display library and crystal structure modeling, a stem fragment immunogen, located at the turning point of the HA neck undergoing conformational change during membrane fusion with both B- and T-cell epitopes, was identified. After synthesis of the optimal stem fragment using a multiple antigen peptide (MAP) system, strong humoral immune responses and cross-clade neutralizing activities against strains from the H3 subtype of group 2 influenza viruses after animal immunizations were observed. By detection of nuclear protein immunofluorescence with acid bypass treatment, antisera raised against MAP4 immunogens of the stem fragment showed the potential to inhibit the conformational change of HA in stem-targeted virus neutralization. The identification of this conserved stem fragment provides great potential for exploitation of this site of vulnerability in therapeutic and vaccine design.


Immunology Letters | 2015

Elicitation of HIV-1 neutralizing antibodies by presentation of 4E10 and 10E8 epitopes on Norovirus P particles.

Yongjiao Yu; Lu Fu; Yuhua Shi; Shanshan Guan; Lan Yang; Xin Gong; He Yin; Xiaoqiu He; Dongni Liu; Ziyu Kuai; Yaming Shan; Song Wang; Wei Kong

Eliciting efficient broadly neutralizing antibodies (BnAbs) is a major goal in vaccine development against human immunodeficiency virus type 1 (HIV-1). Conserved epitopes in the membrane-proximal external region (MPER) of HIV-1 are a significant target. In this study, Norovirus P particles (NoV PPs) were used as carriers to display conformational 4E10 and 10E8 epitopes in different patterns with an appropriate linker. Immune responses to the recombinant NoV PPs were characterized in guinea pigs and Balb/c mice and could induce high levels of MPER-binding antibodies. Modest neutralizing activities could be detected in sera of guinea pigs but not of Balb/c mice. The 4E10 or 10E8 epitopes dispersed on three loops on the outermost surface of NoV PPs (4E10-loop123 PP or 10E8-loop123 PP) elicited higher neutralizing activities than the equivalent number of epitopes presented on loop 2 only (4E10-3loop2 PP or 10E8-3loop2 PP). The epitopes on different loops of the PP were well-exposed and likely formed an appropriate conformation to induce neutralizing antibodies. Although sera of immunized guinea pigs could neutralize several HIV envelope-pseudoviruses, a vaccine candidate for efficiently inducing HIV-1 BnAbs remains to be developed.


Scientific Reports | 2017

Exploration of binding and inhibition mechanism of a small molecule inhibitor of influenza virus H1N1 hemagglutinin by molecular dynamics simulation

Shanshan Guan; Tianao Wang; Ziyu Kuai; Mengdan Qian; Xiaopian Tian; Xiuqi Zhang; Yongjiao Yu; Song Wang; Hao Zhang; Hao Li; Wei Kong; Yaming Shan

Influenza viruses are a major public health threat worldwide. The influenza hemagglutinin (HA) plays an essential role in the virus life cycle. Due to the high conservation of the HA stem region, it has become an especially attractive target for inhibitors for therapeutics. In this study, molecular simulation was applied to study the mechanism of a small molecule inhibitor (MBX2329) of influenza HA. Behaviors of the small molecule under neutral and acidic conditions were investigated, and an interesting dynamic binding mechanism was found. The results suggested that the binding of the inhibitor with HA under neutral conditions facilitates only its intake, while it interacts with HA under acidic conditions using a different mechanism at a new binding site. After a series of experiments, we believe that binding of the inhibitor can prevent the release of HA1 from HA2, further maintaining the rigidity of the HA2 loop and stabilizing the distance between the long helix and short helices. The investigated residues in the new binding site show high conservation, implying that the new binding pocket has the potential to be an effective drug target. The results of this study will provide a theoretical basis for the mechanism of new influenza virus inhibitors.


RSC Advances | 2016

Potential of a novel peptide P16-D from the membrane-proximal external region of human immunodeficiency virus type 1 to enhance retrovirus infection

Huayan Zhang; Xiaoqiu He; Yuhua Shi; Yongjiao Yu; Shanshan Guan; Xin Gong; He Yin; Ziyu Kuai; Yaming Shan

The peptide P13 (Ac-671NWFDITNWLWYIK683-NH2), derived from the membrane-proximal external region (MPER) of the human immunodeficiency virus type 1 (HIV-1) transmembrane protein and its derivative P16, have been shown to significantly boost HIV-1 infectivity by forming amyloid fibrils. Here, a new modified nanofibril peptide P16-D derived from P16 was demonstrated to have an enhanced ability to promote retroviral gene transfer. Moreover, the “networks” formed by P16-D nanofibrils could effectively capture and concentrate enveloped virus by low-speed centrifugation. In addition, the captured influenza virus H1N1 could elicit a stronger immune response in mice at a lower dose than that in the absence of the nanofibrils. The results implied a potential for P16-D to improve gene transfer rates and vaccine applications.


RSC Advances | 2018

Humanization and directed evolution of the selenium-containing scFv phage abzyme

Yan Xu; Pengju Li; Jiaojiao Nie; Qi Zhao; Shanshan Guan; Ziyu Kuai; Yongbo Qiao; Xiaoyu Jiang; Ying Li; Wei Li; Yuhua Shi; Wei Kong; Yaming Shan

According to the binding site structure and the catalytic mechanism of the native glutathione peroxidase (GPX), three glutathione derivatives, GSH-S-DNP butyl ester (hapten Be), GSH-S-DNP hexyl ester (hapten He) and GSH-S-DNP hexamethylene ester (hapten Hme) were synthesized. By a four-round panning with a human synthetic scFv phage library against three haptens, the enrichment of the scFv phage particles with specific binding activity could be determined. Three phage particles were selected binding to each glutathione derivative, respectively. After a two-step chemical mutation to convert the serine residues of the scFv phage particles into selenocysteine residues, GPX activity could be observed and determined upto 3000 U μmol−1 in the selenium-containing scFv phage abzyme which was isolated by affinity capture against the hapten Be. Also the scFv phage abzymes elicited by different antigens displayed different catalytic activities. After a directed evolution by DNA shuffling to improve the affinity to the hapten Be, a secondary library with GPX activity was created in which the catalytic activity of the selenium-containing scFv phage abzyme could be increased 17%. This study might be helpful for new haptens or antigens design to optimize the abzymes with high binding activities and might also provide a novel scheme for GPX mimic candidates for drug development.


Journal of Cellular Physiology | 2018

Effects of poly(I:C) and MF59 co-adjuvants on immunogenicity and efficacy of survivin polypeptide immunogen against melanoma

Xiaoyu Jiang; Shanshan Guan; Yongbo Qiao; Xiao Li; Yan Xu; Lan Yang; Ziyu Kuai; Haihong Zhang; Yuhua Shi; Wei Kong; Yaming Shan; Hao Zhang

Malignant tumors pose a public health problem that jeopardizes human life and quality of living. At present, tumor vaccines in clinical research typically are aimed at stimulating the cellular immune response, while more effective vaccines should take into account the synergy between broad spectrum antibodies and high levels of cellular immunity. In this study, epitope peptides (68–81, 95–104, 80–88) of the tumor antigen survivin were chosen as immunogens and supplemented with poly(I:C) and/or MF59 adjuvant to evaluate the immune effects and anti‐melanoma activities. The results indicated that poly(I:C) and MF59 could assist the survivin epitope peptide immunogen to control the tumor size, quality, and volume in black melanoma mouse models. Analyses by antibody titering, antibody isotyping and ELISPOT suggested that the adjuvanted immunogen could induce humoral immunity in mice. Poly(I:C) and MF59 combined with survivin peptide 95–104 could effectively induce humoral immunity mediated by type 2 T helper (Th2) cells. This study provides a basis for candidate immunogen design based on survivin and provides support for tumor therapy that can induce a more balanced Th1/Th2 immune response.

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