Membrane protein association by potential intrarnembrane charge pairs

Cosson, Pierre; Lankford, Scott P.; Bonifacino, Juan S.; Klausner, Richard D.

doi:10.1038/351414a0

Cited by 233 publications

(170 citation statements)

References 16 publications

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“…where ij are the Miyazawa and Jernigan (25) contact energies between residue i and j, f ij is a distance function with the general shape of a ''soft'' Lennard-Jones potential (a 6-4 potential in agreement with the multiatomic nature of the virtual "atoms" used in this representation, unlike the atomistic 12-6 Lennard-Jones function), arom is an aromatic-clustering factor highlighting aromatic-aromatic interactions, cat is a cation-interaction factor reflecting what is recognized as an important noncovalent binding interaction in ␣-helical peptides (26), and polar is a polar-polar interaction factor that emphasizes their contribution in agreement with studies that point to specific polar interactions implicated in driving TM helix association (27,28), especially in the hydrophilic core of GPCRs. The protein-membrane interaction term E membrane(Res i , Z i ) is a function of the chemical character of Res i and its position Z i in the direction normal to the membrane plane.…”

Section: Methodsmentioning

confidence: 49%

G protein-coupled receptors:In silicodrug discovery in 3D

Becker¹,

Marantz²,

Shacham³

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

164

158

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The application of structure-based in silico methods to drug discovery is still considered a major challenge, especially when the x-ray structure of the target protein is unknown. Such is the case with human G protein-coupled receptors (GPCRs), one of the most important families of drug targets, where in the absence of x-ray structures, one has to rely on in silico 3D models. We report repeated success in using ab initio in silico GPCR models, generated by the PREDICT method, for blind in silico screening when applied to a set of five different GPCR drug targets. More than 100,000 compounds were typically screened in silico for each target, leading to a selection of <100 ''virtual hit'' compounds to be tested in the lab. In vitro binding assays of the selected compounds confirm high hit rates, of 12-21% (full dose-response curves, K i < 5 M). In most cases, the best hit was a novel compound (New Chemical Entity) in the 1-to 100-nM range, with very promising pharmacological properties, as measured by a variety of in vitro and in vivo assays. These assays validated the quality of the hits as lead compounds for drug discovery. The results demonstrate the usefulness and robustness of ab initio in silico 3D models and of in silico screening for GPCR drug discovery.modeling ͉ in silico screening ͉ structure-based G protein-coupled receptors (GPCRs) are membraneembedded proteins, responsible for communication between the cell and its environment (1). As a consequence, many major diseases, such as hypertension, cardiac dysfunction, depression, anxiety, obesity, inflammation, and pain, involve malfunction of these receptors (2), making them among the most important drug targets for pharmacological intervention (3-5). Thus, whereas GPCRs are only a small subset of the human genome, they are the targets for Ϸ50% of all recently launched drugs (6). As targets of paramount importance, it is expected that drug discovery for GPCRs would benefit from the introduction of computational methodologies (7), especially as these methods can be used in conjunction with such experimental methods as high-throughput screening (8, 9), NMR, and crystallography (10).Unfortunately, GPCRs, like other membrane-embedded proteins, have characteristics that make their 3D structure extremely difficult to determine experimentally. To date, the only GPCR for which a 3D structure was determined by x-ray crystallography is bovine rhodopsin (11), which is unique among GPCRs in that its ligand, retinal, is covalently bound and that it responds to light rather than to ligand binding. Hence, in the case of GPCRs, the limited availability of structural data has forced the computational design of ligands to heavily rely on ligand-based techniques. Indeed, for many GPCRs, the natural ligand can provide a good starting point, leading to useful pharmacophore models that can be used for identifying lead structures with novel scaffolds (6). These methods have been successfully applied for the discovery of peptide agonists to the somatostatin receptor (12) and for...

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Section: Methodsmentioning

confidence: 49%

G protein-coupled receptors:In silicodrug discovery in 3D

Becker¹,

Marantz²,

Shacham³

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

164

158

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“…Similarly, CD3 and z proteins each contain a single aspartic or glutamic acid in their TM domains, creating a pair of acidic residues in each dimeric module. Cellular transfection studies established that at least some of these ionizable residues participate in assembly (Alcover et al 1990;Blumberg et al 1990a;Cosson et al 1991;Manolios et al 1991). A more comprehensive mutagenesis analysis using in vitro-assembled complexes revealed that each of the basic TM residues in the TCR specifically recruits one of the three signaling modules in contacts requiring both acidic TM residues (Call et al 2002;Call et al 2004).…”

Section: Mechanisms Directing Tcr-cd3 Complex Assemblymentioning

confidence: 99%

Structural Biology of the T-cell Receptor: Insights into Receptor Assembly, Ligand Recognition, and Initiation of Signaling

Wucherpfennig¹,

Gagnon²,

Call³

et al. 2010

Cold Spring Harbor Perspectives in Biology

154

108

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The T-cell receptor (TCR)-CD3 complex serves as a central paradigm for general principles of receptor assembly, ligand recognition, and signaling in the immune system. There is no other receptor system that matches the diversity of both receptor and ligand components. The recent expansion of the immunological structural database is beginning to identify key principles of MHC and peptide recognition. The multicomponent assembly of the TCR complex illustrates general principles used by many receptors in the immune system, which rely on basic and acidic transmembrane residues to guide assembly. The intrinsic binding of the cytoplasmic domains of the CD31 and z chains to the inner leaflet of the plasma membrane represents a novel mechanism for control of receptor activation: Insertion of critical CD31 tyrosines into the hydrophobic membrane core prevents their phosphorylation before receptor engagement. LIGAND BINDING BY THE EXTRACELLULAR DOMAINS OF T-CELL RECEPTORS: STRUCTURAL BASIS OF ab AND gd TCR BINDING TO A DIVERSE GROUP OF LIGANDST he structures of many T-cellreceptors (TCRs) in their ligand-bound state have now been determined, allowing some of the general rules of antigen recognition to be distilled. Though the best studied interaction is the binding of abTCR with peptide-MHC complexes, it is highly instructive to compare the prototypical binding to peptide-MHC with the recognition of lipid antigen-CD1 complexes and engagement of nonclassical MHC class I molecules by gdTCRs. These comparisons show that the recognition strategies for these

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“…Single amino acid changes in the TM region have been reported in other studies to affect the assembly of receptors with FcR-␥ chain or the homologous CD3 chain. Mutation of the TM potentially charged aspartic acid in FcR-␥, CD3 , and Fc␥RIII, or Fc⑀RI abrogates assembly of these subunits into receptor complexes (45)(46)(47). Likewise, among the LRC receptors, the TM arginine residue has been shown for Fc␣RI (Arg 209 ) and gpVI (Arg 272 ) to be essential for assembly with the FcR-␥ chain (6,7,22,23).…”

Section: Association Of Fcr-␥ and Fc␣ri Subunits-transmembranementioning

confidence: 99%

Fc Receptor γ Chain Residues at the Interface of the Cytoplasmic and Transmembrane Domains Affect Association with FcαRI, Surface Expression, and Function

Wines

Trist

Monteiro

et al. 2004

Journal of Biological Chemistry

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The assembly of multiple subunit immunoreceptors is dependent on transmembrane interactions. The Fc receptor ␥ (FcR-␥) chain is a ubiquitous immune receptor tyrosine-based activation motif-containing dimeric subunit, ␥ 2 , which in humans associates with both the activating members of the leukocyte receptor cluster, including the IgA receptor Fc␣RI, and the classical Fc receptors, including the IgE receptor Fc⑀RI. This study identifies a new site in the transmembrane region of FcR-␥ that affects receptor assembly and surface expression with Fc␣RI but not with Fc⑀RI. The wild type complex, Fc␣RI-␥ 2 WT, remains robustly associated in both Brij-96 and Thesit detergent conditions. However, mutation of either Tyr 25 or Cys 26 of FcR-␥, near the interface of the transmembrane and cytoplasmic regions, resulted in impaired FcR-␥ association with Fc␣RI. This association was disrupted in the presence of the detergent Brij-96 but was preserved in milder conditions using the detergent Thesit. Ligand-mediated cross-linking of the Fc␣RI-␥ 2 Y25F mutant receptor resulted in diminished signal transduction, including an abnormal calcium response, compared with the Fc␣RI-␥ 2 WT receptor. Furthermore, the Fc␣RI-␥ 2 Y25F mutant receptor was expressed at the cell surface at ϳ10% of that of the wild type, whereas the surface expression of Fc⑀RI-␥ 2 Y25F was not significantly different from the wild type. In contrast, although the Fc␣RI-␥ 2 C26S mutant was also less stably associated, it was not reduced in surface expression or function. Thus, these TM residues of FcR-␥ are important for association with Fc␣RI and probably other activating LRC members but not with the classical FcR, Fc⑀RI.

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Membrane protein association by potential intrarnembrane charge pairs

Cited by 233 publications

References 16 publications

G protein-coupled receptors:In silicodrug discovery in 3D

G protein-coupled receptors:In silicodrug discovery in 3D

Structural Biology of the T-cell Receptor: Insights into Receptor Assembly, Ligand Recognition, and Initiation of Signaling

Fc Receptor γ Chain Residues at the Interface of the Cytoplasmic and Transmembrane Domains Affect Association with FcαRI, Surface Expression, and Function

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