Crystal Structure of Canine and Bovine Granulocyte-Colony Stimulating Factor (G-CSF)

Lovejoy, Brett; Cascio, Duilio; Eisenberg, David

doi:10.1006/jmbi.1993.1617

Cited by 56 publications

(52 citation statements)

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“…For example, interactions involving Tyr-22 were altered in pMC5H relative to mIL-6, suggesting the N-and C-termini are in close proximity. This is consistent with the structures of related cytokines such as IL-4 (Walter et al, 1992), GM-CSF (Diederichs et al, 1992), and G-CSF (Lovejoy et al, 1992), which place the N-and C-termini in close proximity. The proximity of the N-and C-termini of hIL-6 was also suggested by Brakenhoff et al (1990) on the basis of epitope mapping studies of a series of neutralizing Mabs.…”

Section: Discussionsupporting

confidence: 86%

Role of the C‐terminus in the activity, conformation, and stability of interleukin‐6

et al. 1993

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Two murine interleukin-6 (mIL-6) variants were constructed using the polymerase chain reaction (PCR), one lacking the last five residues (183-187) at the C-terminus (pMC5) and another with the last five residues of mIL-6 substituted by the corresponding residues of human IL-6 (pMC5H). The growth stimulatory activity of pMC5 on the mouse hybridoma cell line 7TD1 was <0.05% of mIL-6, whereas pMC5H and mIL-6 were equipotent. The loss of biological activity of pMCS correlated with its negligible receptor binding affinity on 7TD1 cells, while the binding of pMC5H was comparable to that of mIL-6. Both pMC5 and pMCSH, like mIL-6, failed to interact with recombinant soluble human IL-6 receptor when assayed by surface plasmon resonance-based biosensor analysis. These studies suggest that the C-terminal seven amino acids of human IL-6, alone, do not define species specificity for receptor binding.A variety of biophysical techniques, as well as the binding of a conformational-specific monoclonal antibody, indicated that the global fold of the mIL-6 variants was similar to that of mIL-6, although small changes in the NMR spectra, particularly for pMC5, were observed. Some of these changes involved residues widely separated in the primary structure. For instance, interactions involving Tyr-22 were influenced by the C-terminal amino acids suggesting that the N-and C-termini of mIL-6 are in close proximity. Equilibrium unfolding experiments indicated that pMC5 was 0.8 kcal/mol less stable than mIL-6, whereas pMCSH was 1.4 kcal/mol more stable. These studies emphasize the structural importance of the C-terminal amino acids of IL-6 and suggest that truncation or mutation of this region could lead to small but significant alterations in other regions of the molecule.

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Section: Discussionsupporting

confidence: 86%

Role of the C‐terminus in the activity, conformation, and stability of interleukin‐6

et al. 1993

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“…Data from such models allow us to begin to predict regions of interaction between HuIFNaX and each of the receptor proteins. The structure of murine interferon-@ (MuIFNP) is similar to the experimentally determined structures of other a-helical cytokines, which includes HGH (de Vos et al, 1992), porcine growth hormones 19X7), GM-CSF (Diederichs et al, 1991;Walter et al, 1992a), granulocyte colony-stimulating factor (G-CSF) (Hill et al, 1993;Lovejoy et al, 1993), macrophage colony-stimulating factor (M-CSF) (Pandit et al, 1992), IL-2 (Brandhuber et al,19X7), IL-4 (Redfield et al, 1991;Powers et al, 1992;Smith et al, 1992;Walter et al, 1992b;Wlodawer et al, 1992), and IL-5 (Milburn et al, 1993). The common structural motif among these cytokines is a left-handed four a-helix bundle with an up-up-downdown topology (Presnell & Cohen, 1989;Mitsui et al, 1993).…”

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confidence: 64%

Homology model of human interferon‐α8 and its receptor complex

Seto¹,

Harkins²,

Adler³

et al. 1995

Protein Science

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Human interferond (HuIFNa8), a type I interferon (IFN), is a cytokine belonging to the hematopoietic superfamily that includes human growth hormone (HGH). Recent data identified two human type I IFN receptor components. One component (p40) was purified from human urine by its ability to bind to immobilized type I IFN. A second receptor component (IFNAR), consisting of two cytokine receptor-like domains (D200 and D200'), was identified by expression cloning. Murine cells transfected with a gene encoding this protein were able to produce an antiviral response to human IFNa8. Both of these receptor proteins have been identified as members of the immunoglobulin superfamily of which H G H receptor is a member. The cytokine receptor-like structural motifs present in p40 and IFNAR were modeled based on the HGH receptor X-ray structure. Models of the complexes of HuIFNa8 with the receptor subunits were built by superpositioning the conserved C a backbone of the HuIFNa8 and receptor subunit models with HGH and its receptor complex. The HuIFNa8 model was constructed from the Ca coordinates of murine interferon-p crystal structure. Electrostatic potentials and hydrophobic interactions appear to favor the model of HuIFNa8 interacting with p40 at site 1 and the D200' domain of IFNAR at site 2 because there are regions of complementary electrostatic potential and hydrophobic interactions at both of the proposed binding interfaces. Some of the predicted receptor binding residues within HuIFNa8 correspond to functionally important residues determined previously for human IFNal, IFNa2, and IFNa4 subtypes by site-directed mutagenesis studies. The models predict regions of interaction between HuIFNa8 and each of the receptor proteins, and provide insights into interactions between other type I IFNs (IFN-a subtypes and IFN-p) and their respective receptor components.

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“…The fact that these nearby charged sidechains do not significantly affect the pK, values of the histidines may reflect the possibility that this region of the structure is flexible in solution. In the X-ray structures of GH [14], IL-2 [31] and G-CSF [15,32] part of the CD loop cannot be seen in the electron density, suggesting that this is a mobile region in these molecules. Analysis of the last 22 ps of the dynamics trajectory of the hLIF model in water indicates that the N-terminus and the N-terminal region of the CD loop are amongst the most variable parts of the structure.…”

Section: Discussionmentioning

confidence: 94%

Homology modelling and ¹H NMR studies of human leukaemia inhibitory factor

et al. 1994

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Human leukaemia inhibitory factor (LIF) is a glycoprotein with a diverse range of activities on many cell types. A molecular model of LIF has been constructed based mainly on the structure of the related cytokine granulocyte colony-stimulating factor, and refined using simulated annealing and molecular dynamics in water. The model was stable during molecular dynamics refinement and is consistent with known stereochemical data on proteins. It has been assessed by comparison with ~H NMR data on the ionization behaviour of the six histidine residues in LIF, the imidazolium pKa values of which range from 3.6 to 7.4. These pKa values were assigned to individual histidine residues from NMR studies on a series of His --* Ala mutants. The environments of the histidine residues in the model account very well for their observed ionization behaviour. Furthermore, the model is consistent with mutagenesis studies which have defined a group of amino acid residues involved in receptor binding.

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Crystal Structure of Canine and Bovine Granulocyte-Colony Stimulating Factor (G-CSF)

Cited by 56 publications

References 0 publications

Role of the C‐terminus in the activity, conformation, and stability of interleukin‐6

Role of the C‐terminus in the activity, conformation, and stability of interleukin‐6

Homology model of human interferon‐α8 and its receptor complex

Homology modelling and ¹H NMR studies of human leukaemia inhibitory factor

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Crystal Structure of Canine and Bovine Granulocyte-Colony Stimulating Factor (G-CSF)

Cited by 56 publications

References 0 publications

Role of the C‐terminus in the activity, conformation, and stability of interleukin‐6

Role of the C‐terminus in the activity, conformation, and stability of interleukin‐6

Homology model of human interferon‐α8 and its receptor complex

Homology modelling and 1H NMR studies of human leukaemia inhibitory factor

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Homology modelling and ¹H NMR studies of human leukaemia inhibitory factor