ORCID Profile
0000-0001-8940-3663
Current Organisation
National Institutes of Health
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Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2767-9764.C.6551150
Abstract: The tumor-associated antigen mesothelin is expressed at high levels on the cell surface of many human cancers, while its expression in normal tissues is limited. The binding of mesothelin to the tumor-associated cancer antigen 125 (CA-125) can lead to heterotypic cell adhesion and tumor metastasis within the pleural and peritoneal cavities. Immunotherapeutic strategies targeting mesothelin are being intensively investigated. Here, we report the crystal structures of mesothelin that reveal a compact, right-handed solenoid consisting of 24 short helices and connecting loops. These helices form a nine-layered spiral coil that resembles ARM/HEAT family proteins. Glycan attachments have been identified in the structure for all three predicted N-glycosylation sites and confirmed with s les from cell culture and patient ascites. The structures of full-length mesothelin and its complex with the Fab of MORAb-009 reveal the interaction of the antibody with the complete epitope, which has not been reported previously. The N-terminal half of mesothelin is conformationally rigid, suitable for eliciting specific antibodies, whereas its C-terminal portion is more flexible. The structure of the C-terminal shedding-resistant fragment of mesothelin complexed with a mAb 15B6 displays an extended linear epitope and helps explain the protection afforded by the antibody for the shedding sites. Significance: The structures of full-length mesothelin and its complexes with antibodies reported here are the first to be determined experimentally, providing atomic models for structural organization of this protein and its interactions with antibodies. It offers insights into the function of mesothelin and guidance for further development of therapeutic antibodies. /
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2767-9764.22546337.V1
Abstract: Comparison of experimental MSLN structure with those of computational models.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2767-9764.22546334
Abstract: Mapping epitopes of monoclonal antibodies to the structure of MSLN.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2767-9764.22546340.V1
Abstract: Arrangement of MSLN molecules in the crystal.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2767-9764.22546334.V1
Abstract: Mapping epitopes of monoclonal antibodies to the structure of MSLN.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2767-9764.22546331
Abstract: Table S1: Plasmids and primers used for protein expression. Table S2: Characterization of MSLN expression constructs. Table S3: Structural alignments of MSLN models. Table S4: Lists of interactions. Table S5: Buried surface area for three MSLN-Fab complexes. Table S6: Observed saccharide attachments at predicted glycosylation sites. Table S7: Dali search result.
Publisher: American Association for Cancer Research (AACR)
Date: 02-2023
DOI: 10.1158/2767-9764.CRC-22-0306
Abstract: The tumor-associated antigen mesothelin is expressed at high levels on the cell surface of many human cancers, while its expression in normal tissues is limited. The binding of mesothelin to the tumor-associated cancer antigen 125 (CA-125) can lead to heterotypic cell adhesion and tumor metastasis within the pleural and peritoneal cavities. Immunotherapeutic strategies targeting mesothelin are being intensively investigated. Here, we report the crystal structures of mesothelin that reveal a compact, right-handed solenoid consisting of 24 short helices and connecting loops. These helices form a nine-layered spiral coil that resembles ARM/HEAT family proteins. Glycan attachments have been identified in the structure for all three predicted N-glycosylation sites and confirmed with s les from cell culture and patient ascites. The structures of full-length mesothelin and its complex with the Fab of MORAb-009 reveal the interaction of the antibody with the complete epitope, which has not been reported previously. The N-terminal half of mesothelin is conformationally rigid, suitable for eliciting specific antibodies, whereas its C-terminal portion is more flexible. The structure of the C-terminal shedding-resistant fragment of mesothelin complexed with a mAb 15B6 displays an extended linear epitope and helps explain the protection afforded by the antibody for the shedding sites. The structures of full-length mesothelin and its complexes with antibodies reported here are the first to be determined experimentally, providing atomic models for structural organization of this protein and its interactions with antibodies. It offers insights into the function of mesothelin and guidance for further development of therapeutic antibodies.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2767-9764.22546340
Abstract: Arrangement of MSLN molecules in the crystal.
Publisher: Springer Science and Business Media LLC
Date: 20-09-2018
DOI: 10.1007/S12104-018-9841-4
Abstract: The C-terminal domain of the P protein of rabies virus is a multifunctional domain that interacts with both viral and host cell proteins. Here we report the
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2767-9764.22546337
Abstract: Comparison of experimental MSLN structure with those of computational models.
Publisher: Proceedings of the National Academy of Sciences
Date: 05-05-2022
Abstract: Mesothelin (MSLN) is a cell-surface protein that is a popular target for antibody-based therapies. We have identified shed MSLN as a major obstacle to successful antibody therapies and prepared a monoclonal antibody that inhibits shedding and makes very active CAR T cells whose activity is not blocked by shed MSLN and merits further preclinical development.
Publisher: American Society for Microbiology
Date: 11-05-2022
DOI: 10.1128/JVI.00111-22
Abstract: Rabies virus P protein is a multifunctional protein with critical roles in replication and manipulation of host-cell processes, including subversion of immunity. This functional ersity involves interactions of several P protein isoforms with the cell nucleus and microtubules.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2767-9764.C.6551150.V1
Abstract: The tumor-associated antigen mesothelin is expressed at high levels on the cell surface of many human cancers, while its expression in normal tissues is limited. The binding of mesothelin to the tumor-associated cancer antigen 125 (CA-125) can lead to heterotypic cell adhesion and tumor metastasis within the pleural and peritoneal cavities. Immunotherapeutic strategies targeting mesothelin are being intensively investigated. Here, we report the crystal structures of mesothelin that reveal a compact, right-handed solenoid consisting of 24 short helices and connecting loops. These helices form a nine-layered spiral coil that resembles ARM/HEAT family proteins. Glycan attachments have been identified in the structure for all three predicted N-glycosylation sites and confirmed with s les from cell culture and patient ascites. The structures of full-length mesothelin and its complex with the Fab of MORAb-009 reveal the interaction of the antibody with the complete epitope, which has not been reported previously. The N-terminal half of mesothelin is conformationally rigid, suitable for eliciting specific antibodies, whereas its C-terminal portion is more flexible. The structure of the C-terminal shedding-resistant fragment of mesothelin complexed with a mAb 15B6 displays an extended linear epitope and helps explain the protection afforded by the antibody for the shedding sites. Significance: The structures of full-length mesothelin and its complexes with antibodies reported here are the first to be determined experimentally, providing atomic models for structural organization of this protein and its interactions with antibodies. It offers insights into the function of mesothelin and guidance for further development of therapeutic antibodies. /
Publisher: Springer Science and Business Media LLC
Date: 11-10-2023
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2767-9764.22546331.V1
Abstract: Table S1: Plasmids and primers used for protein expression. Table S2: Characterization of MSLN expression constructs. Table S3: Structural alignments of MSLN models. Table S4: Lists of interactions. Table S5: Buried surface area for three MSLN-Fab complexes. Table S6: Observed saccharide attachments at predicted glycosylation sites. Table S7: Dali search result.
Publisher: Frontiers Media SA
Date: 13-03-2023
DOI: 10.3389/FCHEM.2023.1146753
Abstract: The mitochondrial respiratory chain has long been a primary target for the development of fungicides for its indispensable role in various cellular functions including energy metabolism. Over the years, a wide range of natural and synthetic fungicides and pesticides targeting the respiratory chain complexes have been discovered or developed and used in agriculture and in medicine, which brought considerable economic gains but was also accompanied by the emergence of resistance to these compounds. To delay and overcome the onset of resistance, novel targets for fungicides development are actively being pursued. Mitochondrial AAA protein Bcs1 is necessary for the biogenesis of respiratory chain Complex III, also known as cyt bc 1 complex, by delivering the last essential iron-sulfur protein subunit in its folded form to the cyt bc 1 precomplex. Although no report on the phenotypes of knock-out Bcs1 has been reported in animals, pathogenic Bcs1 mutations cause Complex III deficiency and respiratory growth defects, which makes it a promising new target for the development of fungicides. Recent Cryo-EM and X-ray structures of mouse and yeast Bcs1 revealed the basic oligomeric states of Bcs1, shed light on the translocation mechanism of its substrate ISP, and provided the basis for structure-based drug design. This review summarizes the recent progress made on understanding the structure and function of Bcs1, proposes the use of Bcs1 as an antifungal target, and provides novel prospects for fungicides design by targeting Bcs1.
Publisher: Public Library of Science (PLoS)
Date: 08-07-2021
DOI: 10.1371/JOURNAL.PPAT.1009729
Abstract: Rabies virus phosphoprotein (P protein) is a multifunctional protein that plays key roles in replication as the polymerase cofactor that binds to the complex of viral genomic RNA and the nucleoprotein (N protein), and in evading the innate immune response by binding to STAT transcription factors. These interactions are mediated by the C-terminal domain of P (P CTD ). The colocation of these binding sites in the small globular P CTD raises the question of how these interactions underlying replication and immune evasion, central to viral infection, are coordinated and, potentially, coregulated. While direct data on the binding interface of the P CTD for STAT1 is available, the lack of direct structural data on the sites that bind N protein limits our understanding of this interaction hub. The P CTD was proposed to bind via two sites to a flexible loop of N protein (N pep ) that is not visible in crystal structures, but no direct analysis of this interaction has been reported. Here we use Nuclear Magnetic Resonance, and molecular modelling to show N protein residues, Leu381, Asp383, Asp384 and phosphor-Ser389, are likely to bind to a ‘positive patch’ of the P CTD formed by Lys211, Lys214 and Arg260. Furthermore, in contrast to previous predictions we identify a single site of interaction on the P CTD by this N pep . Intriguingly, this site is proximal to the defined STAT1 binding site that includes Ile201 to Phe209. However, cell-based assays indicate that STAT1 and N protein do not compete for P protein. Thus, it appears that interactions critical to replication and immune evasion can occur simultaneously with the same molecules of P protein so that the binding of P protein to activated STAT1 can potentially occur without interrupting interactions involved in replication. These data suggest that replication complexes might be directly involved in STAT1 antagonism.
No related grants have been discovered for Jingyu Zhan.