Crystallographic Studies of Chemokines, Chemokine Receptors, and Related Protein

趋化因子、趋化因子受体和相关蛋白质的晶体学研究

• 批准号: 7594833
• 负责人: Jacek T Lubkowski
• 金额: $ 34.61万
• 依托单位: DIVISION OF CLINICAL SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7594833
• 关键词: Acquired Immunodeficiency Syndrome; Antibiotics; Binding; CCR6 gene; Chemistry; Collaborations; Data; Defensins; Disease; Drug resistance; Epitopes; Goals; HDAC6 gene; Human; Knowledge; Ligands; Molecular; Organism; Papillomavirus; Papillomavirus Infections; Peptides; Property; Proteins; Publishing; Rationalization; Receptor Activation; Route; Topical agent; alpha-Defensins; antimicrobial; base; beta-Defensins; chemokine; chemokine receptor; design; novel; prevent; receptor; receptor function

One of the most significant accomplishments was to show a strong inhibitory properties of human defensin 5 (HD5) against the papillomaviruses. These properties make HD5 a potential candidate for the topical agent in preventing the papillomavirus infection. This year we also published the first structural data on three human alpha-defensis, HNP4, HD5, and HD6. This accomplishments makes all human alpha-defensins structurally characterized. In the other study, we published the preliminary draft of the epitope in the human beta-defensin molecules, that is responsible for binding and/or activating the chemokine receptor, CCR6. In continuation of this effort, whcih is near-complete, we identified more details on the structural determinants of beta-defensins, whcih are necessary for productive interaction with CCR6. We also showed that one of these proteins, hBD4, does not activate CCR6 and explained, in detail, the reason for this defficiency. In collaboration with Dr. Lu, we studies two other aspects of human alpha-defensins' chemistry: high ratio of Arg (as compared to Lys) in their sequences, the phenomenon not observed for beta-defensins, and effect of the pro-region, in a pro-peptide form, for the folding efficiency of human alpha-defensins. In both cases, we provided a rationalization, based largery on structural studies.

其中最重要的成就之一是显示出人防御素5(HD5)对乳头状瘤病毒的强烈抑制特性。这些特性使HD5成为预防乳头瘤病毒感染的潜在候选外用药物。今年，我们还首次公布了三种人类阿尔法基因HNP4、HD5和HD6的结构数据。这一成就使所有人类阿尔法防御素都具有结构性特征。在另一项研究中，我们公布了人类β-防御素分子中负责结合和/或激活趋化因子受体CCR6的表位的初稿。在这项接近完成的努力的继续中，我们确定了关于β-防御素结构决定因素的更多细节，这对于与CCR6进行有效的相互作用是必要的。我们还证明了其中一种蛋白质hBD4不能激活CCR6，并详细解释了这种缺陷的原因。与卢博士合作，我们研究了人类α-防御素化学的另外两个方面：在其序列中高比例的精氨酸(与赖氨酸相比)，在β-防御素中没有观察到的现象，以及前肽形式的前区域对人类α-防御素折叠效率的影响。在这两种情况下，我们都提供了基于结构研究的合理化建议。