Structural Basis for Allosteric Regulation of GPCRs by Sodium Ions

被引:977
|
作者
Liu, Wei [1 ]
Chun, Eugene [1 ]
Thompson, Aaron A. [1 ]
Chubukov, Pavel [1 ]
Xu, Fei [1 ]
Katritch, Vsevolod [1 ]
Han, Gye Won [1 ]
Roth, Christopher B. [2 ]
Heitman, Laura H. [3 ]
IJzerman, Adriaan P. [3 ]
Cherezov, Vadim [1 ]
Stevens, Raymond C. [1 ]
机构
[1] Scripps Res Inst, Dept Mol Biol, La Jolla, CA 92037 USA
[2] Receptos, San Diego, CA 92121 USA
[3] Leiden Amsterdam Ctr Drug Res, Div Med Chem, NL-2300 RA Leiden, Netherlands
基金
荷兰研究理事会;
关键词
ADENOSINE A(2A) RECEPTOR; CRYSTAL-STRUCTURE; OPIOID RECEPTOR; MODULATION; RHODOPSIN; COMPLEX; AMILORIDE; RESIDUES; SITE;
D O I
10.1126/science.1219218
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Pharmacological responses of G protein-coupled receptors (GPCRs) can be fine-tuned by allosteric modulators. Structural studies of such effects have been limited due to the medium resolution of GPCR structures. We reengineered the human A(2A) adenosine receptor by replacing its third intracellular loop with apocytochrome b(562)RIL and solved the structure at 1.8 angstrom resolution. The high-resolution structure allowed us to identify 57 ordered water molecules inside the receptor comprising three major clusters. The central cluster harbors a putative sodium ion bound to the highly conserved aspartate residue Asp(2.50). Additionally, two cholesterols stabilize the conformation of helix VI, and one of 23 ordered lipids intercalates inside the ligand-binding pocket. These high-resolution details shed light on the potential role of structured water molecules, sodium ions, and lipids/cholesterol in GPCR stabilization and function.
引用
收藏
页码:232 / 236
页数:6
相关论文
共 50 条
  • [31] Structural basis for allosteric regulation of human ribonucleotide reductase by nucleotide-induced oligomerization
    Fairman, James Wesley
    Wijerathna, Sanath Ranjan
    Ahmad, Md Faiz
    Xu, Hai
    Nakano, Ryo
    Jha, Shalini
    Prendergast, Jay
    Welin, R. Martin
    Flodin, Susanne
    Roos, Annette
    Nordlund, Par
    Li, Zongli
    Walz, Thomas
    Dealwis, Chris Godfrey
    NATURE STRUCTURAL & MOLECULAR BIOLOGY, 2011, 18 (03) : 316 - U102
  • [32] Structural Basis for the Allosteric Regulation and Substrate Recognition of Human Cytosolic 5′-Nucleotidase II
    Wallden, Karin
    Nordlund, Par
    JOURNAL OF MOLECULAR BIOLOGY, 2011, 408 (04) : 684 - 696
  • [33] Structural basis for allosteric regulation of human ribonucleotide reductase by nucleotide-induced oligomerization
    James Wesley Fairman
    Sanath Ranjan Wijerathna
    Md Faiz Ahmad
    Hai Xu
    Ryo Nakano
    Shalini Jha
    Jay Prendergast
    R Martin Welin
    Susanne Flodin
    Annette Roos
    Pär Nordlund
    Zongli Li
    Thomas Walz
    Chris Godfrey Dealwis
    Nature Structural & Molecular Biology, 2011, 18 : 316 - 322
  • [34] Structural basis for allosteric regulation of pyruvate kinase M2 by phosphorylation and acetylation
    Nandi, Suparno
    Razzaghi, Mortezaali
    Srivastava, Dhiraj
    Dey, Mishtu
    JOURNAL OF BIOLOGICAL CHEMISTRY, 2020, 295 (51) : 17425 - 17440
  • [35] Structural Basis of the Lactate-dependent Allosteric Regulation of Oxygen Binding in Arthropod Hemocyanin
    Hirota, Shun
    Tanaka, Naoki
    Micetic, Ivan
    Di Muro, Paolo
    Nagao, Satoshi
    Kitagishi, Hiroaki
    Kano, Koji
    Magliozzo, Richard S.
    Peisach, Jack
    Beltramini, Mariano
    Bubacco, Luigi
    JOURNAL OF BIOLOGICAL CHEMISTRY, 2010, 285 (25) : 19338 - 19345
  • [36] Structural basis for tumor pyruvate kinase M2 allosteric regulation and catalysis
    Dombrauckas, JD
    Santarsiero, BD
    Mesecar, AD
    BIOCHEMISTRY, 2005, 44 (27) : 9417 - 9429
  • [37] Structural Basis for Tumor Pyruvate Kinase M2 Allosteric Regulation and Catalysis
    Dombrauckas, Jill D.
    Santarsiero, Bernard D.
    Mesecar, Andrew D.
    ACTA CRYSTALLOGRAPHICA A-FOUNDATION AND ADVANCES, 2005, 61 : C186 - C186
  • [38] Binding Leverage as a Molecular Basis for Allosteric Regulation
    Mitternacht, Simon
    Berezovsky, Igor N.
    PLOS COMPUTATIONAL BIOLOGY, 2011, 7 (09)
  • [39] Structural basis of efficacy-driven ligand selectivity at GPCRs
    Alexander S. Powers
    Vi Pham
    Wessel A. C. Burger
    Geoff Thompson
    Yianni Laloudakis
    Nicholas W. Barnes
    Patrick M. Sexton
    Steven M. Paul
    Arthur Christopoulos
    David M. Thal
    Christian C. Felder
    Celine Valant
    Ron O. Dror
    Nature Chemical Biology, 2023, 19 : 805 - 814
  • [40] Structural basis of efficacy-driven ligand selectivity at GPCRs
    Powers, Alexander S.
    Pham, Vi
    Burger, Wessel A. C.
    Thompson, Geoff
    Laloudakis, Yianni
    Sexton, Patrick M.
    Paul, Steven M.
    Christopoulos, Arthur
    Thal, David M.
    Felder, Christian C.
    Valant, Celine
    Dror, Ron O.
    NATURE CHEMICAL BIOLOGY, 2023, 19 (07) : 805 - +