A5014060935- Fibroblast Growth Factor Research
- Cell death mechanisms and regulation
- RNA Interference and Gene Delivery
- Cancer-related Molecular Pathways
- Eosinophilic Disorders and Syndromes
- Epigenetics and DNA Methylation
- Drug Transport and Resistance Mechanisms
- Neuroendocrine Tumor Research Advances
- Peptidase Inhibition and Analysis
- Liver physiology and pathology
- Liver Diseases and Immunity
- Nuclear Receptors and Signaling
- Pregnancy and Medication Impact
- FOXO transcription factor regulation
- Ubiquitin and proteasome pathways
- Hepatitis B Virus Studies
- interferon and immune responses
- Monoclonal and Polyclonal Antibodies Research
- Retinoids in leukemia and cellular processes
- Immune Cell Function and Interaction
- Genomics and Chromatin Dynamics
- Cholangiocarcinoma and Gallbladder Cancer Studies
- T-cell and B-cell Immunology
- Protein Degradation and Inhibitors
- Histone Deacetylase Inhibitors Research
Central South University
2019-2025
Xiangya Hospital Central South University
2019-2025
Shanghai Jiao Tong University
2016-2017
Tongren Hospital
2016-2017
Sichuan University
2008
Abstract Mitochondrial apoptosis is strictly controlled by BCL-2 family proteins through a subtle network of protein interactions. The tumor suppressor p53 triggers transcription-independent direct interactions with proteins, but the molecular mechanism not well understood. In this study, we present three crystal structures p53-DBD in complex anti-apoptotic at resolutions 2.3–2.7 Å. show that two loops penetrate directly into BH3-binding pocket BCL-2. Structure-based mutations interface...
Abstract The use of antibodies to target immune checkpoints, particularly PD-1/PD-L1, has made a profound impact in the field cancer immunotherapy. Here, we identified KN035, an anti-PD-L1 nanobody that can strongly induce T-cell responses and inhibit tumor growth. crystal structures KN035 complexed with PD-L1 free PD-L1, solved here at 1.7 2.7 Å resolution, respectively, show competes PD-1 (programmed death protein 1) for same flat surface on mainly through single loop 21 amino acids. This...
Abstract The tumor suppressor p53 is mutated in approximately half of all human cancers. can induce apoptosis through mitochondrial membrane permeabilization by interacting with and antagonizing the anti-apoptotic proteins BCL-xL BCL-2. However, mechanisms which induces remain elusive. Here, we report a 2.5 Å crystal structure p53/BCL-xL complex. In this structure, two molecules interact as homodimer, bind one molecule to form ternary complex 2:1 stoichiometry. Mutations at dimer interface...
Abstract The aryl hydrocarbon receptor (AHR), a member of the basic helix–loop–helix (bHLH) Per–Arnt–Sim (PAS) family transcription factors, plays important roles in regulating xenobiotic metabolism, cellular differentiation, stem cell maintenance, as well immunity. More recently, AHR has gained significant interest drug target for development novel cancer immunotherapy drugs. Detailed understanding AHR-ligand binding been hampered decades by lack three-dimensional structure PAS-B domain....
Bispecific antibodies provide an efficient tool for combinational clinical therapy. Here we have engineered a heterodimeric Fc bispecific production by combining the knob-into-hole and electrostatic steering strategies where bulky hydrophobic residue Phe405 of IgG CH3 interface is mutated to charged Lys Lys409 corresponding domain Ala. The crystal structure this heterodimer solved here at 2.7Å resolution revealed how these two mutations resulted complementary binding explained why F405K...
Forkhead transcription factors bind a canonical consensus DNA motif, RYAAAYA (R = A/G, Y C/T), as monomer. However, the molecular mechanisms by which forkhead dimer are not well understood. In this study, we show that FOXO1 recognizes palindromic element DIV2, and mediates transcriptional regulation. The crystal structure of FOXO1/DIV2 reveals binding domain (DBD) binds DIV2 site homodimer. wing1 region dimerization, enhances affinity complex stability. Further biochemical assays FOXO3,...
Fibroblast growth factor receptor (FGFR) dysregulation is involved in a variety of tumorigenesis and development. Cholangiocarcinoma closely related with FGFR aberrations, pemigatinib the first drug approved to target for treatment cholangiocarcinoma. Herein, we undertake biochemical structural analysis on against FGFRs as well gatekeeper mutations. The results show that potent selective FGFR1-3 inhibitor. extensive network hydrogen bonds van der Waals contacts found FGFR1-pemigatinib...
Farnesoid X receptor (FXR) is a ligand-activated transcription factor known as bile acid (BAR). FXR plays critical roles in various biological processes, including metabolism, immune inflammation, liver regeneration and carcinogenesis. forms heterodimer with the retinoid (RXR) binds to diverse response elements (FXREs) exert its functions. However, mechanism by which FXR/RXR DNA remains unclear. In this study, we aimed use structural, biochemical bioinformatics analyses study of binding...
Abstract Acquired drug resistance poses a challenge for single-target FGFR inhibitors, leading to the development of dual- or multi-target inhibitors. Sulfatinib is kinase inhibitor treating neuroendocrine tumors, selectively targeting FGFR1/CSF-1R. To elucidate molecular mechanisms behind its binding and selectivity, we determined crystal structures sulfatinib with The results reveal common structural features distinct conformational adaptability in response FGFR1/CSF-1R binding. Further...
The FOXC family of transcription factors (FOXC1 and FOXC2) plays essential roles in the regulation embryonic, ocular, cardiac development. Mutations abnormal expression proteins are implicated genetic diseases as well cancer. In this study, we determined two crystal structures DNA-binding domain (DBD) human FOXC2 protein, complex with different DNA sites. FOXC2-DBD adopts winged-helix fold helix H3 contributing to all base specific contacts, while N-terminus, wing 1, C-terminus make...
Hyperactive c-Met signaling pathway caused by altered MET is a common mechanism underlying gastric cancer and represents an attractive target for the treatment of with alterations. However, no kinase inhibitors are currently approved specifically c-Met-amplified cancer. Recently, bozitinib, highly selective inhibitor, has shown remarkable potency in selectively inhibiting MET-altered non-small cell lung secondary glioblastoma. In this study, we investigate antitumor activity bozitinib...
FIIN-2, TAS-120 (Futibatinib) and PRN1371 are highly potent pan-FGFR covalent inhibitors targeting the p-loop cysteine of FGFR proteins, which currently in clinical trials. It is critical to analyze their target selectivity abilities overcome gatekeeper mutations. In this study, we demonstrate that FIIN-2 form adducts with SRC, while does not. inhibit SRC YES activities, Moreover, exhibit different potencies against mutants. addition, co-crystal structures SRC/FIIN-2, SRC/TAS-120...
The fibroblast growth factor 19 (FGF19)/fibroblast receptor 4 (FGFR4) signaling pathways play critical roles in a variety of cancers, such as hepatocellular carcinoma (HCC). FGFR4 is recognized promising target to treat HCC. Currently, all FGFR covalent inhibitors one the two cysteines (Cys477 and Cys552). Here, we designed synthesized dual-warhead inhibitor, CXF-009, targeting Cys477 Cys552 FGFR4. We report cocrystal structure with which exhibits binding mode. CXF-009 exhibited stronger...
Abstract Class IIa Histone deacetylases (HDACs), including HDAC4, 5, 7 and 9, play key roles in multiple important developmental differentiation processes. Recent studies have shown that class HDACs exert their transcriptional repressive function by interacting with tissue-specific transcription factors, such as members of the myocyte enhancer factor 2 (MEF2) family factors. However, molecular mechanism is not well understood. In this study, we determined crystal structure an HDAC4–MEF2A–DNA...
Proteins of nuclear receptor subfamily 4 group A (NR4A), including NR4A1/NGFI-B, NR4A2/Nurr1, and NR4A3/NOR-1, are transcription factors that play important roles in metabolism, apoptosis, proliferation. NR4A proteins recognize DNA response elements as monomers or dimers to regulate the a variety genes involved multiple biological processes. In this study, we determined two crystal structures NR4A2 DNA-binding domain (NR4A2-DBD) bound Nur-responsive elements: an inverted repeat everted at...
The apoptotic pathway is regulated by protein-protein interactions between members of the Bcl-2 family. Pro-survival family proteins act as cell guardians and protect cells against death. Selective binding neutralization BH3-only with pro-survival critical for initiating apoptosis. In this study, assay shows that BH3 peptide derived from protein Bmf has a high affinity Bcl-xL, but much lower Mcl-1. complex structures Bcl-2, Bcl-xL Mcl-1 reveal α-helical accommodates into canonical groove...