Department of Integrative Biology and Physiology, University of Minnesota, 2231 6(th) St. SE, Minneapolis, MN, USA.
Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes, Digestive and Kidney Diseases, NIH, Phoenix, AZ, USA.
Cell Rep. 2019 Sep 3;28(10):2567-2580.e6. doi: 10.1016/j.celrep.2019.07.101.
Structural and functional diversity of peptides and GPCR result from long evolutionary processes. Even small changes in sequence can alter receptor activation, affecting therapeutic efficacy. We conducted a structure-function relationship study on the neuropeptide TLQP-21, a promising target for obesity, and its complement 3a receptor (C3aR1). After having characterized the TLQP-21/C3aR1 lipolytic mechanism, a homology modeling and molecular dynamics simulation identified the TLQP-21 binding motif and C3aR1 binding site for the human (h) and mouse (m) molecules. mTLQP-21 showed enhanced binding affinity and potency for hC3aR1 compared with hTLQP-21. Consistently, mTLQP-21, but not hTLQP-21, potentiates lipolysis in human adipocytes. These findings led us to uncover five mutations in the C3aR1 binding pocket of the rodent Murinae subfamily that are causal for enhanced calculated affinity and measured potency of TLQP-21. Identifying functionally relevant peptide/receptor co-evolution mechanisms can facilitate the development of innovative pharmacotherapies for obesity and other diseases implicating GPCRs.
肽和 G 蛋白偶联受体（GPCR）的结构和功能多样性是经过漫长的进化过程产生的。即使序列的微小变化也可能改变受体的激活，从而影响治疗效果。我们对神经肽 TLQP-21 及其互补 3a 受体（C3aR1）进行了结构-功能关系研究，TLQP-21 是肥胖的一个有前途的治疗靶点。在对 TLQP-21/C3aR1 的脂肪分解机制进行了特征描述后，同源建模和分子动力学模拟确定了 TLQP-21 与人（h）和鼠（m）分子的 C3aR1 结合基序和结合位点。与 hTLQP-21 相比，mTLQP-21 对 hC3aR1 的结合亲和力和效力增强。一致地，mTLQP-21 而非 hTLQP-21 增强了人脂肪细胞的脂肪分解。这些发现使我们在啮齿动物 Murinae 亚科的 C3aR1 结合口袋中发现了五个突变，这些突变导致 TLQP-21 的计算亲和力和实测效力增强。鉴定功能相关的肽/受体协同进化机制可以促进针对肥胖症和其他涉及 GPCR 的疾病的创新药物治疗的发展。
