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Titolo:
The TXP motif in the second transmembrane helix of CCR5 - A structural determinant of chemokine-induced activation
Autore:
Govaerts, C; Blanpain, C; Deupi, X; Ballet, S; Ballesteros, JA; Wodak, SJ; Vassart, G; Pardo, L; Parmentier, M;
Indirizzi:
Free Univ Brussels, Inst Rech Interdisciplinary Biol Humaine & Nucl, B-1070 Brussels, Belgium Free Univ Brussels Brussels Belgium B-1070 ucl, B-1070 Brussels, Belgium Univ Autonoma Barcelona, Fac Med, Unitat Bioestadist, Lab Med Computac, Bellaterra 08193, Spain Univ Autonoma Barcelona Bellaterra Spain 08193 , Bellaterra 08193, Spain Free Univ Brussels, Serv Conformat Macromol Biol, B-1050 Brussels, BelgiumFree Univ Brussels Brussels Belgium B-1050 iol, B-1050 Brussels, Belgium Novasite Pharmaceut Inc, San Diego, CA 92121 USA Novasite Pharmaceut Inc San Diego CA USA 92121 c, San Diego, CA 92121 USA
Titolo Testata:
JOURNAL OF BIOLOGICAL CHEMISTRY
fascicolo: 16, volume: 276, anno: 2001,
pagine: 13217 - 13225
SICI:
0021-9258(20010420)276:16<13217:TTMITS>2.0.ZU;2-R
Fonte:
ISI
Lingua:
ENG
Soggetto:
PROTEIN-COUPLED RECEPTORS; MEMBRANE-SPANNING SEGMENT; BINDING-SITE CREVICE; MONOCYTE CHEMOTACTIC PROTEIN-1; BETA(2) ADRENERGIC-RECEPTOR; SMALL-MOLECULE INHIBITOR; DOPAMINE D2 RECEPTOR; ALPHA-HELICES; CONFORMATIONAL-CHANGES; HIV-1 ENTRY;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
59
Recensione:
Indirizzi per estratti:
Indirizzo: Parmentier, M Free Univ Brussels, Inst Rech Interdisciplinary Biol Humaine& Nucl, Campus Erasme,808 Route Lennik, B-1070 Brussels, Belgium Free UnivBrussels Campus Erasme,808 Route Lennik Brussels Belgium B-1070
Citazione:
C. Govaerts et al., "The TXP motif in the second transmembrane helix of CCR5 - A structural determinant of chemokine-induced activation", J BIOL CHEM, 276(16), 2001, pp. 13217-13225

Abstract

CCR5 is a G-protein-coupled receptor activated by the chemokines RANTES (regulated on activation normal T cell expressed and secreted), macrophage inflammatory protein Icu and Ip, and monocyte chemotactic protein 2 and is the main co-receptor for the macrophage-tropic human immunodeficiency virus strains. We have identified a sequence motif (TXP) in the second transmembrane helix of chemokine receptors and investigated its role by theoretical and experimental approaches. Molecular dynamics simulations of model cy-helices in a nonpolar environment were used to show that a TXP motif strongly bends these helices, due to the coordinated action of the proline, which kinks the helix, and of the threonine, which further accentuates this structural deformation. Site-directed mutagenesis of the corresponding Pro and Thr residues in CCR5 allowed us to probe the consequences of these structural findings in the context of the whole receptor. The P84A mutation leads to a decreased binding affinity for chemokines and nearly abolishes the functional response of the receptor. In contrast, mutation of Thr-82(2.56) into Val,Ala, Cys, or Ser does not affect chemokine binding. However, the functional response was found to depend strongly on the nature of the substituted side chain. The rank order of impairment of receptor activation is P84A > T82V > T82A > T82C > T82S. This ranking of impairment parallels the bending ofthe alpha -helix observed in the molecular simulation study.

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Documento generato il 19/01/20 alle ore 21:01:31