The structure of MCP-1 in two crystal forms provides a rare example of variable quaternary interactions

Łubkowski, J.; Bujacz, G.; Boqué, L.; Domaille, Peter J.; Handel, Tracy M.; Wlodawer, Alexander

doi:10.1038/nsb0197-64

Cited by 145 publications

(159 citation statements)

References 40 publications

Supporting

Mentioning

148

Contrasting

Order By: Relevance

“…The naturally cleaved forms of MCP-2 and RANTES are also devoid of bioactivity (31,34). The function of chemokines has also been further clarified from crystal structure determination and nuclear magnetic resonance data (42)(43)(44)(45)(46)(47)(48)(49)(50)(51)(52)(53)(54)(55)(56). In several chemokines such as IL-8, MCP-1, MCP-2, MCP-3, eotaxin, RANTES, MIP-1␣, MIP-1␤, fractalkine, and stromal cell-derived factor-1, it has been observed that the N-terminal region is essential for functional activity and that the loop immediately following the first two cysteines in the sequence, as well as the N-terminal region, plays an important role in receptor binding.…”

Section: Discussionmentioning

confidence: 99%

Antagonist of Secondary Lymphoid-Tissue Chemokine (CCR Ligand 21) Prevents the Development of Chronic Graft-Versus-Host Disease in Mice

Sasaki

Hasegawa

Kohno

et al. 2003

The Journal of Immunology

View full text Add to dashboard Cite

The use of receptor antagonists for chemokines is an alternative approach to blocking chemokine actions and has the potential to provide novel therapeutics. We determined the receptor antagonist properties of murine N-terminally truncated secondary lymphoid tissue chemokine (SLC)/6Ckine/CCR ligand 21 analogs and evaluated the preventive effects of SLC antagonists on chronic graft-vs-host disease (GVHD) in a murine model by blocking the homing of donor CCR7-expressing T cells into the recipient’s lymphoid organs. SLC analogs truncated >4 aa residues from the N terminus showed a loss of chemotaxis and Ca2+ influx of CCR7-expressing cells and also inhibited SLC-stimulated chemotaxis and SLC-induced Ca2+ influx completely. To determine whether SLC antagonist inhibits the development of chronic GVHD, chronic GVHD was induced by injecting DBA/2 spleen cells into (C57BL/6 × DBA/2) F1 mice. Total numbers of spleen cells and host B cells, serum levels of IgE, and of total IgG and IgG1 of anti-DNA Abs in SLC antagonist-treated GVHD mice were significantly lower than those in control PBS-treated GVHD mice. This was due to a reduction in the levels of activated donor CD4+ T cells and a decrease in IL-4 production, resulting in a reduction in the numbers of activated host B cells. Therefore, our results suggest that SLC antagonist has beneficial effects for the prevention of chronic GVHD.

show abstract

Section: Discussionmentioning

confidence: 99%

Antagonist of Secondary Lymphoid-Tissue Chemokine (CCR Ligand 21) Prevents the Development of Chronic Graft-Versus-Host Disease in Mice

Sasaki

Hasegawa

Kohno

et al. 2003

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…Based on the structure (33,34) and calculations of the difference in solvent accessibility between monomer and dimer, we identified several candidates for mutation including Tyr 13 , Thr 10 , Val 9 , and Pro 8 ( Fig. 1).…”

Section: Y13a* Affects Receptormentioning

confidence: 99%

“…Above micromolar concentrations many form homodimers, whereas at nanomolar concentrations the monomeric form predominates in solution. High resolution structures of IL-8 (31), MGSA/GRO (32), MCP-1 (33,34), RAN-TES (35,36), and MIP-1␤ (37) have also revealed a striking correlation between chemokine class and mode of dimerization (38), suggesting that dimerization may play an important role in chemokine function. A key question, however, is whether dimerization is required for receptor binding and activation or whether it plays a more subtle role in protein stability, regu-lation, surface presentation and retention, formation of the chemotactic gradient, or other processes unrelated to chemotaxis.…”

mentioning

confidence: 99%

Monomeric Monocyte Chemoattractant Protein-1 (MCP-1) Binds and Activates the MCP-1 Receptor CCR2B

Paavola¹,

Hemmerich²,

Grünberger³

et al. 1998

Journal of Biological Chemistry

184

223

View full text Add to dashboard Cite

To address the role of dimerization in the function of the monocyte chemoattractant protein-1, MCP-1, we mutated residues that comprise the core of the dimerization interface and characterized the ability of these mutants to dimerize and to bind and activate the MCP-1 receptor, CCR2b. One mutant, P8A*, does not dimerize. However, it has wild type binding affinity, stimulates chemotaxis, inhibits adenylate cyclase, and stimulates calcium influx with wild type potency and efficacy. These data suggest that MCP-1 binds and activates its receptor as a monomer. In contrast, Y13A*, another monomeric mutant, has a 100-fold weaker binding affinity, is a much less potent inhibitor of adenylate cyclase and stimulator of calcium influx, and is unable to stimulate chemotaxis. Thus Tyr 13 may make important contacts with the receptor that are required for high affinity binding and signal transduction. We also explored whether a mutant, Chemokines are small secreted proteins that function as intercellular messengers to control migration and activation of specific subsets of leukocytes (1-3). This process is mediated by the interaction of chemokines with seven transmembrane Gprotein-coupled receptors on the surface of target cells. Interest in these proteins was first stimulated by the observation of elevated levels in a number of inflammatory diseases (4, 5) including rheumatoid arthritis (6, 7), arteriosclerosis (8, 9), and asthma (10). Although it is not clear whether excessive production is the cause or consequence of these diseases, the demonstration that neutralizing antibodies (11-13) reduced symptoms in a number of animal models generated optimism that receptor antagonists may have therapeutic benefit (14). Recently, it has been shown that certain chemokine receptors also serve as obligate coreceptors for entry of the human immunodeficiency virus into CD4ϩ cells (15)(16)(17) and that viral replication can be inhibited by the ligands of the coreceptors (18 -21). Thus a wide range of clinically important diseases are associated with chemokines and their receptors, motivating many studies to understand the molecular details of chemokine function.Chemokines have been classified into two major families based on their pattern of cysteine residues, their chromosomal location, and their cell specificities (22). ␣-Chemokines such as IL-8 1 have a conserved CXC cysteine motif and act predominantly on neutrophils, whereas ␤-chemokines have a CC signature and attract monocytes and T-cells. The recently discovered chemokines lymphotactin (23) and fractalkine/neurotactin (24,25) are characterized by C and CX 3 C motifs, respectively, and chemoattract T-cells and NK cells. Mutagenesis studies, particularly of ␣-and ␤-chemokines, have provided some insight into the structural determinants of receptor binding and the specificity of these proteins, but many details have yet to emerge.Considerable effort has been devoted to characterizing the stochiometry of chemokine-receptor complexes because most chemokines oligomerize to an extent tha...

show abstract

“…As in the screen against CCR2b (6), the only other significant effect was observed for 34P35, a mutant containing a proline (49). The figure was generated by using MOLMOL (56).…”

Section: Vv-35kda Contacts Many Of the Same Residues Of Mcp-1 That Con-mentioning

confidence: 99%

Molecular determinants for CC-chemokine recognition by a poxvirus CC-chemokine inhibitor

Seet

Singh

Paavola

et al. 2001

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

View full text Add to dashboard Cite

Poxviruses express a family of secreted proteins that bind with high affinity to chemokines and antagonize the interaction with their cognate G protein-coupled receptors (GPCRs). These viral inhibitors are novel in structure and, unlike cellular chemokine receptors, are able to specifically interact with most, if not all, CC-chemokines. We therefore sought to define the structural features of CC-chemokines that facilitate this broad-spectrum interaction. Here, we identify the residues present on human monocyte chemoattractant protein-1 (MCP-1) that are required for highaffinity interaction with the vaccinia virus 35-kDa CC-chemokine binding protein (VV-35kDa). Not only do these residues correspond to those required for interaction with the cognate receptor CCR2b but they are also conserved among many CC-chemokines. Thus, the results provide a structural basis for the ability of VV-35kDa to promiscuously recognize CC-chemokines and block binding to their receptors.CCR2b ͉ chemokine binding protein ͉ monocyte chemoattractant protein-1 ͉ mutagenesis ͉ surface plasmon resonance

show abstract

The structure of MCP-1 in two crystal forms provides a rare example of variable quaternary interactions

Cited by 145 publications

References 40 publications

Antagonist of Secondary Lymphoid-Tissue Chemokine (CCR Ligand 21) Prevents the Development of Chronic Graft-Versus-Host Disease in Mice

Antagonist of Secondary Lymphoid-Tissue Chemokine (CCR Ligand 21) Prevents the Development of Chronic Graft-Versus-Host Disease in Mice

Monomeric Monocyte Chemoattractant Protein-1 (MCP-1) Binds and Activates the MCP-1 Receptor CCR2B

Molecular determinants for CC-chemokine recognition by a poxvirus CC-chemokine inhibitor

Contact Info

Product

Resources

About