Benzimidazole binding to Haemonchus contortus tubulin: a question of structure

Abstract

Response from R.K. PrichardM. Robinson et al., present an interesting structural analysis. The model that was presented in my review was proposed on the evidence for the role of Phe200 and Phe167 in allowing high-affinity benzimidazole (BZM) binding [1xGenetic variability following selection of Haemonchus contortus with anthelmintics. Prichard, R.K. Trends Parasitol. 2001; 17: 445–453Abstract | Full Text | Full Text PDF | PubMed | Scopus (168)See all References][1]. The evidence that the amino acids Ser166, Phe167, Phe200 and Cys201 cluster together, the importance of having a planar BZM structure in order to obtain high-affinity binding, which could allow a staking interaction of the BZM phenyl ring with the two Phe residues at positions 167 and 200, the location of the approximately parallel B5 and B6 strands containing these residues [2xStructure of the αβ tubulin dimer by electron crystallography. Nogales, E et al. Nature. 1998; 391: 199–203Crossref | PubMed | Scopus (1507)See all References][2] and the loss of high-affinity BZM binding when Phe at either position 200 or 167 becomes substituted with a hydroxy substituent (Tyr). However, the model that was proposed does require experimental analysis; therefore, I welcome their discussion. Robinson and colleagues make valuable comments based on measured separation distances of the Phe–Phe inter-rings and the orientation of the side chain of Cys201 in the crystalline structure obtained following taxol stabilization [2xStructure of the αβ tubulin dimer by electron crystallography. Nogales, E et al. Nature. 1998; 391: 199–203Crossref | PubMed | Scopus (1507)See all References][2] and, in the absence of taxol, these restrictions might not apply. I would welcome further work so that we do understand the BZM binding site better, and hope that the model that I have proposed will stimulate further analysis.