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Singh RP, Singh A, Sirohi HV, et al. Dual binding mode of antithyroid drug methimazole to mammalian heme peroxidases - structural determination of the lactoperoxidase-methimazole complex at 1.97 Å resolution. FEBS Open Bio. 2016;6(7):640-50doi: 10.1002/2211-5463.12051.
Singh, R. P., Singh, A., Sirohi, H. V., Singh, A. K., Kaur, P., Sharma, S., & Singh, T. P. (2016). Dual binding mode of antithyroid drug methimazole to mammalian heme peroxidases - structural determination of the lactoperoxidase-methimazole complex at 1.97 Å resolution. FEBS open bio, 6(7), 640-50. https://doi.org/10.1002/2211-5463.12051
Singh, Rashmi Prabha, et al. "Dual binding mode of antithyroid drug methimazole to mammalian heme peroxidases - structural determination of the lactoperoxidase-methimazole complex at 1.97 Å resolution." FEBS open bio vol. 6,7 (2016): 640-50. doi: https://doi.org/10.1002/2211-5463.12051
Singh RP, Singh A, Sirohi HV, Singh AK, Kaur P, Sharma S, Singh TP. Dual binding mode of antithyroid drug methimazole to mammalian heme peroxidases - structural determination of the lactoperoxidase-methimazole complex at 1.97 Å resolution. FEBS Open Bio. 2016 Jun 14;6(7):640-50. doi: 10.1002/2211-5463.12051. eCollection 2016 Jul. PMID: 27398304; PMCID: PMC4932444.
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FEBS Open Bio. 2016 Jun 14;6(7):640-50. doi: 10.1002/2211-5463.12051. eCollection 2016 Jul.

Dual binding mode of antithyroid drug methimazole to mammalian heme peroxidases - structural determination of the lactoperoxidase-methimazole complex at 1.97 Å resolution.

FEBS open bio

Rashmi Prabha Singh, Avinash Singh, Harsh Vardhan Sirohi, Amit Kumar Singh, Punit Kaur, Sujata Sharma, Tej P Singh

Affiliations

  1. Department of Biophysics All India Institute of Medical Sciences New Delhi India.

PMID: 27398304 PMCID: PMC4932444 DOI: 10.1002/2211-5463.12051

Abstract

Lactoperoxidase (LPO, EC 1.11.1.7) is a member of the mammalian heme peroxidase family which also includes thyroid peroxidase (TPO). These two enzymes have a sequence homology of 76%. The structure of LPO is known but not that of TPO. In order to determine the mode of binding of antithyroid drugs to thyroid peroxidase, we have determined the crystal structure of LPO complexed with an antithyroid drug, methimazole (MMZ) at 1.97 Å resolution. LPO was isolated from caprine colostrum, purified to homogeneity and crystallized with 20% poly(ethylene glycol)-3350. Crystals of LPO were soaked in a reservoir solution containing MMZ. The structure determination showed the presence of two crystallographically independent molecules in the asymmetric unit. Both molecules contained one molecule of MMZ, but with different orientations. MMZ was held tightly between the heme moiety on one side and the hydrophobic parts of the side chains of Arg255, Glu258, and Leu262 on the opposite side. The back of the cleft contained the side chains of Gln105 and His109 which also interacted with MMZ. In both orientations, MMZ had identical buried areas and formed a similar number of interactions. It appears that the molecules of MMZ can enter the substrate-binding channel of LPO in two opposite orientations. But once they reach the distal heme pocket, their orientations are frozen due to equally tight packing of MMZ in both orientations. This is a novel example of an inhibitor binding to an enzyme with two orientations at the same site with nearly equal occupancies.

Keywords: antithyroid drug; crystal structure; distal heme pocket; lactoperoxidase; mammalian heme peroxidases; methimazole

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