Solution structure of recombinant human interleukin-6.
Interleukin-6 (IL-6) is a 185 amino acid cytokine which exerts multiple biological effects in vivo and whose dysregulation underlies several disease processes. The solution structure of recombinant human interleukin-6 has now been determined using heteronuclear three and four-dimensional NMR spectroscopy. The structure of the molecule was determined using 3044 distance and torsion restraints derived by NMR spectroscopy to generate an ensemble of 32 structures using a combined distance geometry/simulated annealing protocol. The protein contains five alpha-helices interspersed with variable-length loops; four of these helices constitute a classical four-helix bundle with the fifth helix located in the CD loop. There were no distance violations greater than 0.3 A in any of the final 32 structures and the ensemble has an average-to-the-mean backbone root-mean-square deviation of 0.50 A for the core four-helix bundle. Although the amino-terminal 19 amino acids are disordered in solution, the remainder of the molecule has a well defined structure that shares many features displayed by other long-chain four-helix bundle cytokines. The high-resolution NMR structure of hIL-6 is used to rationalize available mutagenesis data in terms of a heteromeric receptor complex.
Xu
G Y
GY
Small Molecule Drug Discovery, Genetics Institute, Cambridge, MA 02140, USA.
Yu
H A
HA
Hong
J
J
Stahl
M
M
McDonagh
T
T
Kay
L E
LE
Cumming
D A
DA
D015703:Antigens, CD / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure; D001665:Binding Sites; D006801:Humans; D006860:Hydrogen Bonding; D015850:Interleukin-6 / Q000737:chemistry* / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D016296:Mutagenesis; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D018123:Receptors, Interleukin / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure; D019947:Receptors, Interleukin-6; D011994:Recombinant Proteins; D012996:Solutions; D013329:Structure-Activity Relationship
D015703:Antigens, CD; D015850:Interleukin-6; D018123:Receptors, Interleukin; D019947:Receptors, Interleukin-6; D011994:Recombinant Proteins; D012996:Solutions