title: Common structural interactions between the receptors CXCR3, CXCR4 and CXCR7 complexed with their natural ligands, CXCL11 and CXCL12, by a modeling approach.
abstract: Chemokine receptor trio composed by CXCR3, CXCR4 and CXCR7 represents a hard and interesting challenge for cancer biology because these three receptors are found to be over-expressed in different cancers as well as to bind the same chemokines. In fact, CXCR4 interacts with CXCL12, CXCR7 not only with CXCL12 but also with CXCL11, that is a natural ligand for CXCR3. For these reasons, it seems necessary to define and to identify the structural determinants of CXCR3, CXCR4 and CXCR7 and their related physic-chemical properties that permit them to bind CXCL11 and CXCL12. Hence in this paper we show the modeling of CXCR7 and its complex with CXCL11 and CXCL12 compared to CXCR3/CXCL11 and CXCR4/CXCL12. Our results show that (i) CXCR3, CXCR4 and CXCR7 present similar trans-membrane helices and different conformations of N-terminal and C-terminal regions as well as of three extracellular loops, and (ii) the predominant interaction between the three receptors and the two chemokines are on hydrophobic and electrostatic basis. Moreover, our data confirm that CXCL12 binds to CXCR7 with higher affinity than to CXCR4. Methodologically, we can also conclude that our computational strategy is adequate to model correctly the interactions between these chemokines and their receptors; therefore, our models represent a good structural basis to design and develop peptides able to block contemporaneously CXCR3, CXCR4 and CXCR7 receptor trio.
authors.affiliation: Istituto Nazionale per lo Studio e la Cura dei Tumori, Fondazione Giovanni Pascale, IRCCS, Italy. Electronic address: susan.costantini@unina2.it.
authors.forename: Susan
authors.initials: S
authors.lastname: Costantini
authors.forename: Raffaele
authors.initials: R
authors.lastname: Raucci
authors.forename: Teresa
authors.initials: T
authors.lastname: De Vero
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Castello
authors.forename: Giovanni
authors.initials: G
authors.lastname: Colonna
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002417:Cattle; D045744:Cell Line, Tumor; D054371:Chemokine CXCL11 / Q000378:metabolism*; D054377:Chemokine CXCL12 / Q000378:metabolism*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000378:metabolism; D011485:Protein Binding; D054387:Receptors, CXCR / Q000378:metabolism*; D054367:Receptors, CXCR3 / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000378:metabolism*; D012243:Rhodopsin / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D020539:Sequence Analysis, Protein; D055672:Static Electricity
chemical_list: C501896:ACKR3 protein, human; C515202:CXCL11 protein, human; C515255:CXCL12 protein, human; C515187:CXCR3 protein, human; C527276:CXCR4 protein, human; D054371:Chemokine CXCL11; D054377:Chemokine CXCL12; D054387:Receptors, CXCR; D054367:Receptors, CXCR3; D019718:Receptors, CXCR4; D012243:Rhodopsin
keywords: CXCL11; CXCL12; CXCR3; CXCR4; CXCR7