No abstract

The evolutionary trace (ET) method, a data mining approach for determining significant levels of amino acid conservation, has been applied to over 700 aligned G-protein-coupled receptor (GPCR) sequences. The method predicted the occurrence of functionally important clusters of residues on the external faces of helices 5 and 6 for each family or subfamily of receptors; similar clusters were observed on helices 2 and 3. The probability that these clusters are not random was determined using Monte Carlo techniques. The cluster on helices 5 and 6 is consistent with both 5,6-contact and 5,6-domain swapped dimer formation; the possible equivalence of these two types of dimer is discussed because this relates to activation by homo- and heterodimers. The observation of a functionally important cluster of residues on helices 2 and 3 is novel, and some possible interpretations are given, including heterodimerization and oligomerization. The application of the evolutionary trace method to 113 aligned G-protein sequences resulted in the identification of two functional sites. One large, well-defined site is clearly identified with adenyl cyclase, beta/gamma and regulator of G-protein signaling (RGS) binding. The other G-protein functional site, which extends from the ras-like domain onto the helical domain, has the correct size and electrostatic properties for GPCR dimer binding. The implications of these results are discussed in terms of the conformational changes required in the G-protein for activation by a receptor dimer. Further, the implications of GPCR dimerization for medicinal chemistry are discussed in the context of these ET results.

No abstract

The incidence of nasal polyposis among children 5 to 18 years of age with cystic fibrosis (CF) was investigated with a systematic examination of all children on the local CF register. Out of 23 children with CF, 13 had endoscopic evidence of nasal polyposis. Four children had grade 2 polyposis, and 9 children had grade 3 polyposis. Complete opacity of the maxillary sinus was identified on a computed tomographic sinus scan in all but 2 of the children. Only 1 child had a developed frontal sinus. Between 1989 and 2000, 12 children underwent radical endoscopic sinus surgery for their nasal polyposis. There was good postoperative improvement in all of the children; however, 7 eventually required revision surgery because of recurrence of the nasal polyps. The median interval between repeated sinus surgeries was 4 years (range, 18 months to more than 6 years). This information can help in the counseling of parents when sinus surgery is considered for children with CF.