PDF(Pubmed)
Abstract：
Therapeutic agents targeting cytokine-cytokine receptor (CK-CKR) interactions lead to the disruption in cellular signaling and are effective in treating many diseases including tumors. However, a lack of universal and quick access to annotated structural surface regions on CK/CKR has limited the progress of a structure-driven approach in developing targeted macromolecular drugs and precision medicine therapeutics. Herein we develop CytoSIP (Single nucleotide polymorphisms (SNPs), Interface, and Phenotype), a rich internet application based on a database of atomic interactions around hotspots in experimentally determined CK/CKR structural complexes. CytoSIP contains: (1) SNPs on CK/CKR; (2) interactions involving CK/CKR domains, including CK/CKR interfaces, oligomeric interfaces, epitopes, or other drug targeting surfaces; and (3) diseases and phenotypes associated with CK/CKR or SNPs. The database framework introduces a unique tri-level SIP data model to bridge genetic variants (atomic level) to disease phenotypes (organism level) using protein structure (complexes) as an underlying framework (molecule level). Customized screening tools are implemented to retrieve relevant CK/CKR subset, which reduces the time and resources needed to interrogate large datasets involving CK/CKR surface hotspots and associated pathologies. CytoSIP portal is publicly accessible at https://CytoSIP.biocloud.top , facilitating the panoramic investigation of the context-dependent crosstalk between CK/CKR and the development of targeted therapeutic agents.
摘要：
靶向细胞因子-细胞因子受体(CK-CKR)相互作用的治疗剂导致细胞信号传导的破坏,并且在治疗包括肿瘤的许多疾病中是有效的。然而,缺乏对CK/CKR上有注释的结构表面区域的通用和快速访问限制了结构驱动方法在开发靶向大分子药物和精准医学疗法方面的进展。在这里，我们开发了CytoSIP(单核苷酸多态性(SNPs)，接口,和表型），基于实验确定的CK/CKR结构复合物中热点周围原子相互作用数据库的丰富互联网应用程序。CytoSIP包含：（1）CK/CKR上的SNP；（2）涉及CK/CKR结构域的相互作用，包括CK/CKR接口，寡聚界面，表位,或其他药物靶向表面;和(3)与CK/CKR或SNP相关的疾病和表型。数据库框架引入了独特的三级SIP数据模型，以使用蛋白质结构（复合物）作为基础框架（分子水平）将遗传变异（原子水平）桥接到疾病表型（生物体水平）。实施定制筛选工具以检索相关CK/CKR子集，这减少了询问涉及CK/CKR表面热点和相关病理的大型数据集所需的时间和资源。CytoSIP门户可在https://CytoSIP公开访问。生物云。top,有助于对CK/CKR与靶向治疗剂开发之间的上下文相关串扰进行全景研究。
