The molecular basis for high affinity of a universal ligand for human bombesin receptor (BnR) family members.
The molecular basis for high affinity of a universal ligand for human bombesin receptor (BnR) family members.
复制标题
人铃蟾肽受体 (BnR) 家族成员通用配体高亲和力的分子基础。
DOI：
10.1016/j.bcp.2012.07.010
复制
发表时间：
2012
影响因子：
5.8
通讯作者：
Jensen,RobertT
中科院分区：
文献类型：
--
作者：
Uehara,Hirotsugu;Hocart,SimonJ;González,Nieves;Mantey,SamuelA;Nakagawa,Tomoo;Katsuno,Tatsuro;Coy,DavidH;Jensen,RobertT
There is increased interest in the Bn-receptor family because they are frequently over/ectopically expressed by tumors and thus useful as targets for imaging or receptor-targeted-cytotoxicity. The synthetic Bn-analog, [d-Tyr6, β-Ala11, Phe13, Nle14]Bn(6–14) [Univ.Lig] has the unique property of having high affinity for all three human BNRs (GRPR, NMBR, BRS-3), and thus could be especially useful for this approach. However, the molecular basis of this property is unclear and is the subject of this study. To accomplish this, site-directed mutagenesis was used after identifying potentially important amino acids using sequence homology analysis of all BnRs with high affinity for Univ.Lig compared to the Cholecystokinin-receptor (CCKAR), which has low affinity. Using various criteria 74 amino acids were identified and 101 mutations made in GRPR by changing each to those of CCKAR or to alanine. 22 GRPR mutations showed a significant decrease in affinity for Univ.Lig (>2-fold) with 2 in EC2[D97N, G112V], 1 in UTM6[Y284A], 2 in EC4[R287N, H300S] showing >10-fold decrease in Univ.Lig affinity. Additional mutations were made to explore the molecular basis for these changes. Our results show that high affinity for Univ.Lig by human Bn-receptors requires positively charged amino acids in extracellular (EC)-domain 4 and to a lesser extent EC2 and EC3 suggesting charge-charge interactions may be particularly important for determining the general high affinity of this ligand. Furthermore, transmembrane amino acids particularly in UTM6 are important contributing both charge-charge interactions as well as interaction with a tyrosine residue in close proximity suggesting possible receptor–peptide cation–π or H-bonding interactions are also important for determining its high affinity.
登录
查看更多内容
影响因子：
--
作者：
Chen W. Liaw;D. Grigoriadis;M. Lorang;E. B. D. Souza;Richard A. Maki
通讯作者：
Chen W. Liaw;D. Grigoriadis;M. Lorang;E. B. D. Souza;Richard A. Maki
影响因子：
2.4
作者：
Sancho V;Di Florio A;Moody TW;Jensen RT
通讯作者：
Jensen RT
有效的铃蟾肽受体拮抗剂可区分受体亚型。
DOI：
10.1152/ajpgi.1990.259.3.g468
发表时间：
1990
期刊：
The American journal of physiology
影响因子：
--
作者：
vonSchrenck,T;Wang,LH;Coy,DH;Villanueva,ML;Mantey,S;Jensen,RT
通讯作者：
Jensen,RT
促甲状腺素释放激素 (TRH) 与 TRH 受体跨膜酪氨酸 106 的氢键相互作用。
DOI：
--
发表时间：
1994
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Perlman,JH;Thaw,CN;Laakkonen,L;Bowers,CY;Osman,R;Gershengorn,MC
通讯作者：
Gershengorn,MC
胃泌素释放肽受体羧基末端的丝氨酸和苏氨酸介导内化。
DOI：
10.1016/s0021-9258(20)80726-1
发表时间：
1993
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
R. Benya;Z. Fathi;J. Battey;R. Jensen
通讯作者：
R. Jensen