1. C CA S51 CB S51 Hn Q52 CA S5/S43 CB S5/S43 Hn E44 13 C (ppm) 1 H (ppm) 13 C (ppm) 1 H (ppm) B Figure S1 A ERM AA# A.U SSP score Helix Strand 15 N ERM 38-68 + MED25 (1:0.1)

2. Figure S2 ERM AA#  1 H + 0.2  15 N (ppm) A i3Q54 15 N ERM 38-68 + MED25 (1:0.2) i3Q54 15 N ERM 38-68 + MED25 (1:2) 1H1H 1H1H NH  W57 1H1H 15 N B

3. % Bound 0 100 50 Figure S3 B  Bound Free Delta  k ex (~ K d ) A Delta  k ex (~ K d ) Bound Free

4. Figure S3 ERM/MED25 0.15 0.30 0.50 0.60 0.70 1.00 0.00 ERM/MED25 1.20 1.50 2.00 2.50 3.00 1.00 Gly524 Gly532 Gly436 Gly524 Gly532 Gly436 CD 1H1H 15 N 1H1H Gly532 Gly436 E F 1H1H 15 N 1H1H ERM-bound MED25 Free MED25 ERM-bound MED25

5. K d (µM) Relative CSD (%) n=10 r 2 =-0.97 K d (µM) Relative CSD (%) S525 15 N 1H1H A B Figure S4 15 N MED25 + ERM 38-68 + ERM 38-68 F47L + ERM 38-68 W57L + ERM 38-68 F47L/W57L

6. Figure S5 Intensity ratio Bound/free I/I0 11 22 33 44 55 66 77 11 22 33 ERM 38-68 F47L – MED25 WT 11 44 77 66 22 55 33 33 11 180° AB CD

7. Figure S6 Intensity ratio Bound/free I/I0 11 22 33 44 55 66 77 11 22 33 ERM 38-68 W57L – MED25 WT 44 77 66 55 11 22 33 33 11 180° AB CD

8. 1 H (ppm) 15 N (ppm) Cter-NO° B 1 H (ppm) 15 N (ppm) Nter-NO° A Figure S7

9. ERM 38-68 F47L/W57L - MED25 Q451E 22 55 33 33 11 11 44 77 66 A B 180° CD Figure S8 Intensity ratio Bound/free MED25 11 22 33 44 55 66 77 11 22 33 Q451E MED25 AA#

10. Figure S9 Q451 H499 W57 BA