National Natural Science Foundation of China (NSFC)
81872915
中国
National Natural Science Foundation of China (NSFC)
82073904
中国
National Natural Science Foundation of China (NSFC)
32071203
中国
National Natural Science Foundation of China (NSFC)
81773792
中国
National Natural Science Foundation of China (NSFC)
81973373
中国
National Natural Science Foundation of China (NSFC)
21704064
中国
Ministry of Science and Technology (MoST, China)
2018YFA0507002
中国
引用
ジャーナル: Proc Natl Acad Sci U S A / 年: 2021 タイトル: Molecular insights into differentiated ligand recognition of the human parathyroid hormone receptor 2. 著者: Xi Wang / Xi Cheng / Lihua Zhao / Yuzhe Wang / Chenyu Ye / Xinyu Zou / Antao Dai / Zhaotong Cong / Jian Chen / Qingtong Zhou / Tian Xia / Hualiang Jiang / H Eric Xu / Dehua Yang / Ming-Wei Wang / 要旨: The parathyroid hormone receptor 2 (PTH2R) is a class B1 G protein-coupled receptor (GPCR) involved in the regulation of calcium transport, nociception mediation, and wound healing. Naturally ...The parathyroid hormone receptor 2 (PTH2R) is a class B1 G protein-coupled receptor (GPCR) involved in the regulation of calcium transport, nociception mediation, and wound healing. Naturally occurring mutations in PTH2R were reported to cause hereditary diseases, including syndromic short stature. Here, we report the cryogenic electron microscopy structure of PTH2R bound to its endogenous ligand, tuberoinfundibular peptide (TIP39), and a heterotrimeric G protein at a global resolution of 2.8 Å. The structure reveals that TIP39 adopts a unique loop conformation at the N terminus and deeply inserts into the orthosteric ligand-binding pocket in the transmembrane domain. Molecular dynamics simulation and site-directed mutagenesis studies uncover the basis of ligand specificity relative to three PTH2R agonists, TIP39, PTH, and PTH-related peptide. We also compare the action of TIP39 with an antagonist lacking six residues from the peptide N terminus, TIP(7-39), which underscores the indispensable role of the N terminus of TIP39 in PTH2R activation. Additionally, we unveil that a disease-associated mutation G258D significantly diminished cAMP accumulation induced by TIP39. Together, these results not only provide structural insights into ligand specificity and receptor activation of class B1 GPCRs but also offer a foundation to systematically rationalize the available pharmacological data to develop therapies for various disorders associated with PTH2R.
ダウンロード / ファイル: emd_31405.map.gz / 形式: CCP4 / 大きさ: 42.9 MB / タイプ: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
ボクセルのサイズ
X=Y=Z: 1.045 Å
密度
表面レベル
登録者による: 0.12 / ムービー #1: 0.12
最小 - 最大
-0.40179992 - 0.86658156
平均 (標準偏差)
0.000833783 (±0.023371639)
対称性
空間群: 1
詳細
EMDB XML:
マップ形状
Axis order
X
Y
Z
Origin
0
0
0
サイズ
224
224
224
Spacing
224
224
224
セル
A=B=C: 234.07999 Å α=β=γ: 90.0 °
CCP4マップ ヘッダ情報:
mode
Image stored as Reals
Å/pix. X/Y/Z
1.045
1.045
1.045
M x/y/z
224
224
224
origin x/y/z
0.000
0.000
0.000
length x/y/z
234.080
234.080
234.080
α/β/γ
90.000
90.000
90.000
start NX/NY/NZ
0
0
0
NX/NY/NZ
112
112
112
MAP C/R/S
1
2
3
start NC/NR/NS
0
0
0
NC/NR/NS
224
224
224
D min/max/mean
-0.402
0.867
0.001
-
添付データ
-
試料の構成要素
-
全体 : Parathyroid hormone receptor type 2 in complex with a tuberoinfun...
全体
名称: Parathyroid hormone receptor type 2 in complex with a tuberoinfundibular peptide of 39 residues and G protein
要素
複合体: Parathyroid hormone receptor type 2 in complex with a tuberoinfundibular peptide of 39 residues and G protein
タンパク質・ペプチド: Parathyroid hormone 2 receptor
タンパク質・ペプチド: Tuberoinfundibular peptide of 39 residues
タンパク質・ペプチド: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
タンパク質・ペプチド: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
タンパク質・ペプチド: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
タンパク質・ペプチド: Nanobody-35
リガンド: CHOLESTEROL
リガンド: PALMITIC ACID
-
超分子 #1: Parathyroid hormone receptor type 2 in complex with a tuberoinfun...
超分子
名称: Parathyroid hormone receptor type 2 in complex with a tuberoinfundibular peptide of 39 residues and G protein タイプ: complex / ID: 1 / 親要素: 0 / 含まれる分子: #1-#6