Background: Leucine-rich repeats (LRRs) are present in proteins with diverse functions. The horseshoe-shaped structure of a ribonuclease inhibitor (RI), with a parallel β sheet lining the inner circumference of the horseshoe and α helices flanking its outer circumference, is the only X-ray structure containing these repeats to be determined. Despite the fact that the lengths and sequences of the RI repeats differ from those of the most commonly occurring LRRs, it was deemed worthwhile to derive a three-dimensional structural framework of these more typical LRR proteins, using the RI structure as a template.

Results Sequence alignments of 569 LRRs from 68 proteins were obtained by a profile search and used in a comparative sequence analysis to distinguish between residues with a probable structural role and those which seemed essential for function. This knowledge, along with the known atomic structure of RI, was used to model the three-dimensional structure of the most common LRR units. These modeled units were then used to build the three-dimensional structure of the extracellular domain of the thyrotropin receptor (TSHR) — a ‘typical' LRR protein.

Conclusion The modeled TSHR structure adopts a non-globular arrangement, similar to that in RI. The β regions of this typical LRR protein are the same as in the RI structure, whereas the α helices are shorter and the conformations of the αβ and βα connections are different. As a result of these differences it was not possible to pack together typical LRR units using repeats such as those found in RI. This mutually exclusive relationship is supported by sequence analysis. The predicted structure of the typical LRRs obtained here can be used to build models for any of the known LRR proteins and the approach used for the prediction could be applied to other proteins containing internal repeats.