Journal:Acta Cryst F:S2053230X24010094

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<StructureSection load='' size='450' side='right' scene='underdevelopment' caption=''>
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<StructureSection load='' size='450' side='right' scene='10/1060550/Fig_02/1' caption='Crystal structure of TβRI–SB505124 complex showing the ICD Kinase domain (blue) and SB505124, as spheres with CPK colors, occupying the ATP binding cleft between the kinase N- and C-lobes.'>
===Human TGFβR1 in complex with kinase inhibitor SB505124===
===Human TGFβR1 in complex with kinase inhibitor SB505124===
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<big>Dr Jhon Alexander Rodriguez Buitrago</big> <ref>doi: 10.1107/S2053230X24010094</ref>
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<big>Jhon A. Rodriguez Buitrago, Marene Landstrom, Magnus Wolf-Watz</big> <ref>PMID:39441620</ref>
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<b>Molecular Tour</b><br>
<b>Molecular Tour</b><br>
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Although it is, to an extent, held in check in the industrialized world thanks to antiviral drugs, AIDS is still endemic in many parts of the world, claiming nearly 700,000 lives annually. It is thought that anti-HIV vaccination, when available, will be more efficient against the disease in the long term, especially where regular, well-organized healthcare is lacking. However, HIV mutates rapidly, and stimulating a response that protects against all variants remains challenging. An alternative is to target a host protein, which is essential for the virus to enter cells and produce AIDS.
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Anti-HIV antibody RoAb13 targets a short N-terminal region of the protein CCR5, which is the main entry receptor of HIV into the human organism. Blocking that receptor would, therefore, prevent HIV infection and replication. We had earlier reported the structure of the antibody alone by X-ray crystallography (Chain et al. 2015), but the structure of the antibody complexed to the part of CCR5 to which it binds (its epitope) had remained elusive. That structure is important for designing efficient vaccines based on short synthetic immunogenic peptides that mimic the CCR5 antibody-binding region.
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This study presents the high-resolution crystal structure of the intracellular domain of <scene name='10/1060550/007_9f6x_default_try_2/1'>TGFBR1 in complex with the competitive inhibitor SB505124</scene>. The findings provide detailed insights into this complex's molecular interactions and structural configuration, elucidating the mechanisms by which SB505124 inhibits TGFβR1 activity. These insights are significant for understanding the regulation of TGF-β signaling, a pathway critically involved in cancer biology.
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After a long search for co-crystallization conditions involving both the whole N-terminal region of CCR5 and the minimally required binding region to its antibody (the ‘core peptide’), and the analysis and comparison of X-ray crystallographic electron density maps obtained from several crystals, we have finally located the core peptide of the CCR5 receptor bound to RoAb13. It binds at the hypervariable region ‘CDR3’ of the antibody’s light chain, an expected antigen-binding site. Even though the best attainable resolution is not particularly high at 3 Å, we have been able to identify the interacting residues between antibody and peptide. Furthermore, the core peptide was found to bind to accommodate the full length of the CCR5 N-terminus.
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The manuscript highlights several key points:
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The structural insights thus may inform the design of better peptide analogs for use as immunogens in vivo. These analogs may ultimately provide the basis for active immunization vaccines to stimulate an antibody response to native CCR5, which will thwart HIV infection.
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1. Structural Insights: We reveal the atomic-level <scene name='10/1060550/007_9f6x_default_try_2/2'>interactions between TGFBR1 and SB505124</scene>, offering a comprehensive view of how this inhibitor binds to and affects the receptor's conformation. A comparison of the ICD–SB505124 and ICD–SB431542 complexes is seen in a <scene name='10/1060550/007_fig_3_new_01_png/2'>close-up view</scene>.
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2. Regulatory Mechanisms: The structural analysis sheds light on the functional implications of SB505124 binding, particularly its role in disrupting TGF-β signaling pathways, which are often deregulated in various cancers.
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3. Therapeutic Potential: Based on the structural findings, the potential of SB505124 as a therapeutic agent in cancer treatment is discussed, providing a foundation for future drug development efforts targeting TGFβR1.
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<b>References</b><br>
<b>References</b><br>

Current revision

Crystal structure of TβRI–SB505124 complex showing the ICD Kinase domain (blue) and SB505124, as spheres with CPK colors, occupying the ATP binding cleft between the kinase N- and C-lobes.

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