Binding Mechanism of CD47 with SIRPα Variants and Its Antibody: Elucidated by Molecular Dynamics Simulations
The intricate complex system of the differentiation 47 (CD47) and the signal-regulatory protein alpha (SIRPα) cluster is a crucial target for cancer immunotherapy. Although the conformational state of the CD47-SIRPα complex has been revealed through crystallographic studies, further characterization...
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MDPI AG
2023-06-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/28/12/4610 |
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| author | Kaisheng Huang Yi Liu Shuixiu Wen Yuxin Zhao Hanjing Ding Hui Liu De-Xin Kong |
| author_facet | Kaisheng Huang Yi Liu Shuixiu Wen Yuxin Zhao Hanjing Ding Hui Liu De-Xin Kong |
| author_sort | Kaisheng Huang |
| collection | DOAJ |
| description | The intricate complex system of the differentiation 47 (CD47) and the signal-regulatory protein alpha (SIRPα) cluster is a crucial target for cancer immunotherapy. Although the conformational state of the CD47-SIRPα complex has been revealed through crystallographic studies, further characterization is needed to fully understand the binding mechanism and to identify the hot spot residues involved. In this study, molecular dynamics (MD) simulations were carried out for the complexes of CD47 with two SIRPα variants (SIRPαv1, SIRPαv2) and the commercially available anti-CD47 monoclonal antibody (B6H12.2). The calculated binding free energy of CD47-B6H12.2 is lower than that of CD47-SIRPαv1 and CD47-SIRPαv2 in all the three simulations, indicating that CD47-B6H12.2 has a higher binding affinity than the other two complexes. Moreover, the dynamical cross-correlation matrix reveals that the CD47 protein shows more correlated motions when it binds to B6H12.2. Significant effects were observed in the energy and structural analyses of the residues (Glu35, Tyr37, Leu101, Thr102, Arg103) in the C strand and FG region of CD47 when it binds to the SIRPα variants. The critical residues (Leu30, Val33, Gln52, Lys53, Thr67, Arg69, Arg95, and Lys96) were identified in SIRPαv1 and SIRPαv2, which surround the distinctive groove regions formed by the B2C, C’D, DE, and FG loops. Moreover, the crucial groove structures of the SIRPα variants shape into obvious druggable sites. The C’D loops on the binding interfaces undergo notable dynamical changes throughout the simulation. For B6H12.2, the residues Tyr32<sub>LC</sub>, His92<sub>LC</sub>, Arg96<sub>LC</sub>, Tyr32<sub>HC</sub>, Thr52<sub>HC</sub>, Ser53<sub>HC</sub>, Ala101<sub>HC</sub>, and Gly102<sub>HC</sub> in its initial half of the light and heavy chains exhibit obvious energetic and structural impacts upon binding with CD47. The elucidation of the binding mechanism of SIRPαv1, SIRPαv2, and B6H12.2 with CD47 could provide novel perspectives for the development of inhibitors targeting CD47-SIRPα. |
| first_indexed | 2024-03-11T02:07:48Z |
| format | Article |
| id | doaj.art-ec2f5de0f7344244b2095892e696328c |
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| language | English |
| last_indexed | 2024-03-11T02:07:48Z |
| publishDate | 2023-06-01 |
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| spelling | doaj.art-ec2f5de0f7344244b2095892e696328c2023-11-18T11:47:58ZengMDPI AGMolecules1420-30492023-06-012812461010.3390/molecules28124610Binding Mechanism of CD47 with SIRPα Variants and Its Antibody: Elucidated by Molecular Dynamics SimulationsKaisheng Huang0Yi Liu1Shuixiu Wen2Yuxin Zhao3Hanjing Ding4Hui Liu5De-Xin Kong6State Key Laboratory of Agricultural Microbiology, Agricultural Bioinformatics Key Laboratory of Hubei Province, College of Informatics, Huazhong Agricultural University, Wuhan 430070, ChinaState Key Laboratory of Agricultural Microbiology, Agricultural Bioinformatics Key Laboratory of Hubei Province, College of Informatics, Huazhong Agricultural University, Wuhan 430070, ChinaState Key Laboratory of Agricultural Microbiology, Agricultural Bioinformatics Key Laboratory of Hubei Province, College of Informatics, Huazhong Agricultural University, Wuhan 430070, ChinaState Key Laboratory of Agricultural Microbiology, Agricultural Bioinformatics Key Laboratory of Hubei Province, College of Informatics, Huazhong Agricultural University, Wuhan 430070, ChinaSchool of Basic Medical Sciences, Hubei University of Science and Technology, Xianning 437100, ChinaState Key Laboratory of Agricultural Microbiology, Agricultural Bioinformatics Key Laboratory of Hubei Province, College of Informatics, Huazhong Agricultural University, Wuhan 430070, ChinaState Key Laboratory of Agricultural Microbiology, Agricultural Bioinformatics Key Laboratory of Hubei Province, College of Informatics, Huazhong Agricultural University, Wuhan 430070, ChinaThe intricate complex system of the differentiation 47 (CD47) and the signal-regulatory protein alpha (SIRPα) cluster is a crucial target for cancer immunotherapy. Although the conformational state of the CD47-SIRPα complex has been revealed through crystallographic studies, further characterization is needed to fully understand the binding mechanism and to identify the hot spot residues involved. In this study, molecular dynamics (MD) simulations were carried out for the complexes of CD47 with two SIRPα variants (SIRPαv1, SIRPαv2) and the commercially available anti-CD47 monoclonal antibody (B6H12.2). The calculated binding free energy of CD47-B6H12.2 is lower than that of CD47-SIRPαv1 and CD47-SIRPαv2 in all the three simulations, indicating that CD47-B6H12.2 has a higher binding affinity than the other two complexes. Moreover, the dynamical cross-correlation matrix reveals that the CD47 protein shows more correlated motions when it binds to B6H12.2. Significant effects were observed in the energy and structural analyses of the residues (Glu35, Tyr37, Leu101, Thr102, Arg103) in the C strand and FG region of CD47 when it binds to the SIRPα variants. The critical residues (Leu30, Val33, Gln52, Lys53, Thr67, Arg69, Arg95, and Lys96) were identified in SIRPαv1 and SIRPαv2, which surround the distinctive groove regions formed by the B2C, C’D, DE, and FG loops. Moreover, the crucial groove structures of the SIRPα variants shape into obvious druggable sites. The C’D loops on the binding interfaces undergo notable dynamical changes throughout the simulation. For B6H12.2, the residues Tyr32<sub>LC</sub>, His92<sub>LC</sub>, Arg96<sub>LC</sub>, Tyr32<sub>HC</sub>, Thr52<sub>HC</sub>, Ser53<sub>HC</sub>, Ala101<sub>HC</sub>, and Gly102<sub>HC</sub> in its initial half of the light and heavy chains exhibit obvious energetic and structural impacts upon binding with CD47. The elucidation of the binding mechanism of SIRPαv1, SIRPαv2, and B6H12.2 with CD47 could provide novel perspectives for the development of inhibitors targeting CD47-SIRPα.https://www.mdpi.com/1420-3049/28/12/4610tumor immune responseCD47-SIRPαB6H12.2molecular dynamics simulationbinding mechanismhotspot residue |
| spellingShingle | Kaisheng Huang Yi Liu Shuixiu Wen Yuxin Zhao Hanjing Ding Hui Liu De-Xin Kong Binding Mechanism of CD47 with SIRPα Variants and Its Antibody: Elucidated by Molecular Dynamics Simulations Molecules tumor immune response CD47-SIRPα B6H12.2 molecular dynamics simulation binding mechanism hotspot residue |
| title | Binding Mechanism of CD47 with SIRPα Variants and Its Antibody: Elucidated by Molecular Dynamics Simulations |
| title_full | Binding Mechanism of CD47 with SIRPα Variants and Its Antibody: Elucidated by Molecular Dynamics Simulations |
| title_fullStr | Binding Mechanism of CD47 with SIRPα Variants and Its Antibody: Elucidated by Molecular Dynamics Simulations |
| title_full_unstemmed | Binding Mechanism of CD47 with SIRPα Variants and Its Antibody: Elucidated by Molecular Dynamics Simulations |
| title_short | Binding Mechanism of CD47 with SIRPα Variants and Its Antibody: Elucidated by Molecular Dynamics Simulations |
| title_sort | binding mechanism of cd47 with sirpα variants and its antibody elucidated by molecular dynamics simulations |
| topic | tumor immune response CD47-SIRPα B6H12.2 molecular dynamics simulation binding mechanism hotspot residue |
| url | https://www.mdpi.com/1420-3049/28/12/4610 |
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