Molecular and functional analysis of human β-defensin 3 action at melanocortin receptors.
Molecular and functional analysis of human β-defensin 3 action at melanocortin receptors.
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人类β-防御素 3 对黑皮质素受体作用的分子和功能分析。
DOI：
10.1016/j.chembiol.2013.04.015
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发表时间：
2013
影响因子：
--
通讯作者：
Millhauser,GlennL
中科院分区：
文献类型：
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作者：
Nix,MatthewA;Kaelin,ChristopherB;Ta,Tina;Weis,Allison;Morton,GregoryJ;Barsh,GregoryS;Millhauser,GlennL
β-防御素是一类小的阳离子蛋白质，首先被认为是先天性和适应性免疫系统的抗微生物组分。最近，已发现皮肤中产生的主要β-防御素之一β-防御素3在体内和体外作为黑皮质素受体配体起作用，但其作用的生物物理学和药理学基础一直是谜。在这里，我们报告的功能和生物化学研究集中在人β-防御素3（HBD 3）和黑皮质素受体1和4。遗传学和药理学研究表明，HBD 3作为中性黑皮质素受体拮抗剂，能够阻断刺激性激动剂（如α-黑素细胞刺激激素）或抑制性反向激动剂（如Agouti信号蛋白（ASIP）和Agouti相关蛋白（AGRP））的作用。一个全面的结构-功能分析表明，两个补丁的正电荷残基，位于相反的两极HBD 3和空间组织的紧凑的β-防御素折叠，主要负责高亲和力结合黑皮质素受体。这些发现确定了一个独特的模式，黑皮质素受体-配体相互作用的基础上，主要是静电互补性，与设计的目标黑皮质素和潜在的其他7个跨膜受体的配体的影响。
The β-defensins are a class of small, cationic proteins first recognized as antimicrobial components of the innate and adaptive immune system. More recently, one of the major β-defensins produced in skin, β-defensin 3, has been discovered to function as a melanocortin receptor ligand in vivo and in vitro, but its biophysical and pharmacological basis of action has been enigmatic. Here, we report functional and biochemical studies focused on human β-defensin 3 (HBD3) and melanocortin receptors 1 and 4. Genetic and pharmacologic studies indicate that HBD3 acts as a neutral melanocortin receptor antagonist capable of blocking the action of either stimulatory agonists such as α-melanocyte stimulating hormone or inhibitory inverse agonists such as Agouti signaling protein (ASIP) and Agouti-related protein (AGRP). A comprehensive structure-function analysis demonstrates that two patches of positively charged residues, located on opposite poles of HBD3 and spatially organized by the compact β-defensin fold, are primarily responsible for high-affinity binding to melanocortin receptors. These findings identify a distinct mode of melanocortin receptor-ligand interactions based primarily on electrostatic complementarity, with implications for designing ligands that target melanocortin and potentially other seven transmembrane receptors.