SMRL: Stanford NMR Facility and Resource
HOME INSTRUMENTATION NMR TIME USERS &
RESEARCH		 INDUSTRIAL
AFFILIATES		 NEWS &
LINKS

Millhauser Group Research at the SMRL
Glenn L. Millhauser

Professor
Department of Chemistry and Biochemistry
University of California - Santa Cruz

(831) 459-2176
glennm@chemistry.ucsc.edu

Department Web Page
In collaboration with:

Gregory S. Barsh

Professor
Department of Genetics
Department of Pediatrics - Genetics
Stanford University School of Medicine

(650) 723-5061 and (650) 723-5035
gbarsh@cmgm.stanford.edu

Barsh Group Page

Publications:

Millhauser, GL; McNulty, JC; Jackson, PJ; Thompson, DA; Barsh, GS; Gantz, I (2003) "Loops and links: Structural insights into the remarkable function of the agouti-related protein" MELANOCORTIN SYSTEM, 994 27-35. PDF

Jackson, PJ; McNulty, JC; Yang, YK; Thompson, DA; Chai, BX; Gantz, I; Barsh, GS; Millhauser, GL (2002) "Design, pharmacology, and NMR structure of a minimized cystine knot with agouti-related protein activity" BIOCHEMISTRY, 41 7565-7572. PDF

(Details Below) McNulty, J.C., Thompson, D.A., Bolin, K.A., Wilken, J., Barsh, G.S., and Millhauser, G.L. (2001) "High-Resolution NMR Structure of the Chemically-Synthesized Melanocortin Receptor Binding Domain AGRP(87-132) of the Agouti-Related Protein" Biochemistry, 40 15520-15527. PDF


Details:

High-Resolution NMR Structure of the Chemically-Synthesized Melanocortin Receptor Binding Domain AGRP(87-132) of the Agouti-Related Protein

McNulty, J.C., Thompson, D.A., Bolin, K.A., Wilken, J., Barsh, G.S., and Millhauser, G.L. (2001) Biochemistry ASAP Article. PDF

Abstract: The agouti-related protein (AGRP) is an endogenous antagonist of the melanocortin receptors MC3R and MC4R found in the hypothalamus and exhibits potent orexigenic (appetite-stimulating) activity. The cysteine-rich C-terminal domain of this protein, corresponding to AGRP(87-132), contains five disulfide bonds and exhibits receptor binding affinity and antagonism equivalent to that of the full-length protein. The three-dimensional structure of this domain has been determined by 1H NMR at 800 MHz. The first 34 residues of AGRP(87-132) are well-ordered and contain a three-stranded antiparallel beta sheet, where the last two strands form a beta hairpin. The relative spatial positioning of the disulfide cross-links demonstrates that the ordered region of AGRP(87-132) adopts the inhibitor cystine knot (ICK) fold previously identified for numerous invertebrate toxins. Interestingly, this may be the first example of a mammalian protein assigned to the ICK superfamily. The hairpin's turn region presents a triplet of residues (Arg-Phe-Phe) known to be essential for melanocortin receptor binding. The structure also suggests that AGRP possesses an additional melanocortin-receptor contact region within a loop formed by the first 16 residues of its C-terminal domain. This specific region shows little sequence homology to the corresponding region of the agouti protein, which is an MC1R antagonist involved in pigmentation. Consideration of these sequence differences, along with recent experiments on mutant and chimeric melanocortin receptors, allows us to postulate that this loop in the first 16 residues of its C-terminal domain confers AGRP's distinct selectivity for MC3R and MC4R.

Figure 4 Figure Caption. Family of 40 low-energy structures calculated in CNS at 15 °C. Only backbone atoms are shown. The bonds between backbone atoms are shown in blue; yellow lines represent the disulfides.
Bio-X Structural Biology School of Medicine Stanford University
© Stanford University, All Rights Reserved.