Supplemental Figure 1

1. Supplemental Figure 1 IIa hIL6 MNSFSTSAFGPVAFSLGLLLVLPAAFPAPVPPGEDSKDVAAPHRQPLTSSERIDKQIRYI vIL6 -----MCWFKLWSLLLVGSLLVSGTRG-------------KLPDAPEFEKDLLIQRLNWM hIL6 LDGISALRKETCNKSNMCESSKEALAENNLNLPKMAEKDGCFQSGFNEETCLVKIITGLL vIL6 LWVIDECFRDLCYRTGICKGILEPAAIFHLKLPAINDTDHCGLIGFNETSCLKKLADGFF hIL6 EFEVYLEYLQNRFESSEEQARAVQMSTKVLIQFLQKKAKNLDAITTPDPTTNASLLTKLQ vIL6 EFEVLFKFLTTEFGKSVINVDVMELLTKTLGWDIQEELNKLTKTHYSPPKFDRGLLGRLQ hIL6 AQNQWLQDMTTHLILRSFKEFLQSSLRALRQM---------- vIL6 GLKYWVRHFASFYVLSAMEKFAGQAVRVLDSIPDVTPDVHDK A IIa IIIa Ia A-B loop A B IIb B-C loop C-D loop B C IIIb Ib D Red: Signal peptide Black: Loop Green: Helix

2. Supplemental Figure 2 IIa 52 hIL6 MNSFSTSAFGPVAFSLGLLLVLPAAFPAPVPPGEDSKDVAAPHRQPLTSSE RIDKQIRYI vIL6 -----MCWFKLWSLLLVGSLLVSGTRG-------------KLPDAPEFEKDLLIQRLNWM hIL6 LD GI SALRKETCNKSNMCESSKEALAENNLN LPKMAEKDGCFQSGFNEETCLVKIITGLL vIL6 LWVIDECFRDLCYRTGICKGILEPAAIFHLK LPAINDTDHCGLIGFNETSCLKKLADGFF hIL6 EFEVYLEYLQNRFESSEEQA RAVQMSTKVLIQF LQKKAKNLDAITTPDPTTNASLLTKLQ vIL6 EFEVLFKFLTTEFGKSVINVDVMELLTKTLGWDIQEELNKLTKTHYSPPKFDRGLLGRLQ hIL6 AQNQWLQDMTTHLILRS FKEFLQSSLRALRQM---------- vIL6 GLKYWVRHFASFYVLSAMEKFAGQAVRVLDSIPDVTPDVHDK 34 IIa IIIa 62 65 91 44 47 73 134 153 IIb 135 116 IIIb 181 197 179 163 Red: Signal peptide Black: Loop Green: Helix Bold and marked with brackets: amino acids exchanged in IV5-IV9 (red numbers: IL6, brown numbers vIL6)

3. Supplemental Figure 3 hIL6 MNSFSTSAFGPVAFSLGLLLVLPAAFPAPVPPGEDSKDVAAPHRQPLTSSERIDKQIRYI vIL6 -----MCWFKLWSLLLVGSLLVSGTRG-------------KLPDAPEFEKDLLIQRLNWM 73 hIL6 LDGISA LRKETCNKSNMCESSKEALAENN LNLPKMAEKDGCFQSGFNEETCLVKIITGLL vIL6 LWVIDECFRDLCYRTGICKGILEPAAIFH LKLPAINDTDHCGLIGFNETSCLKKLADGFF 78 89 166 170/171 hIL6 EFEVYLEYLQNRFESSEEQARAVQMSTKVLIQFLQKKAKNLDAITTPDPTTNASLLTKLQ vIL6 EFEVLFKFLTTEFGKSVINVDVMELLTKTLGWDIQEELNKLTKTHYSPPKFDRGLLGRLQ hIL6 AQNQWLQDMTTHLILRSFKEFLQSSLRALRQM---------- vIL6 GLKYWVRHFASFYVLSAMEKFAGQAVRVLDSIPDVTPDVHDK IIIa 67 89 71 49 IIIc 130 142 124 112 IIIb 181 194 176 163 Red: Signal peptide Black: Loop Green: Helix blue: O- and N-glycosylation sites Bold and marked with brackets: amino acids exchanged in IV5-IV9 (red numbers: IL6, brown numbers vIL6)

4. Supplemental Figure 4 A IL6 gp130 IL6R Site III gp130 IL6R Site II IL6 C B Site II a Site II b Gp130 Ig-like-domain Site III c Site III c Site III b Site III a Site I IL6