Developing therapeutic drugs that target peptide receptors is challenging. The structure of one of these G-protein-coupled receptors, NTS1, activated and bound to a peptide, provides an excellent starting point. See Article p.508
Some peptides act as chemical signals between cells, controlling mood, behaviour, stress responses, blood pressure, digestion and cancer progression1. They typically interact with receptor proteins at the cell surface — for example, with the G-protein-coupled receptors (GPCRs) that pass the message on to G proteins inside the cells to induce specific cellular responses. Pharmacological activation of peptide-recognizing GPCRs could thus enable improved therapies to be produced for diseases that involve these receptors. Unfortunately, drug development for these receptors is notoriously difficult, in part owing to the lack of structural information about how the peptide binds or how the receptor is activated. On page 508 of this issue, White et al.2 present the structure of a typical peptide-interacting GPCR (called neurotensin receptor 1), bound to an activating peptide. This work gives the first insight into the mechanisms by which this class of receptor is turned on and will substantially facilitate the design of candidate drugsFootnote 1.
One of the difficulties associated with the discovery of drugs that act on peptide-recognizing GPCRs is that peptides often bind to their target proteins through multiple hydrogen bonds or electrostatic interactions — something that is difficult to replicate in synthetic molecules while maintaining their drug-like properties. Moreover, unlike cytoplasmic proteins, GPCRs are inserted in the cell membrane and are therefore unstable in the aqueous solutions used for the crystallographic techniques that are commonly needed for structure-based drug design.
White and colleagues' structure of the peptide-activated neurotensin receptor 1 (NTS1) is the latest result of a technological revolution that GPCR biochemistry has witnessed in recent years3,4,5,6. It was made possible by several methodological breakthroughs, such as the engineering of GPCRs to create receptors that are more stable than their natural counterparts (by changing specific amino acids or by fusion with other stabilizing proteins), as well as the development of specific conditions for crystallizing membrane proteins (lipidic cubic phase methods).
The overall protein architecture of NTS1 is expected to be representative of the large and, so far, structurally unexplored β-subgroup of GPCRs. More importantly, the structure clarifies how peptide agonists (that is, activators) interact with GPCRs. Until now, peptide agonists had been thought to bind to the extracellular side of their GPCRs, but any further details were unclear. White et al. show that a neurotensin analogue (a peptide similar to neurotensin, NTS1's natural substrate) penetrates deeply into the interior of the receptor like a nail (Fig. 1), albeit not as deeply as non-peptidic agonists do in the GPCRs to which they bind.
Because agonist binding activates GPCRs by inducing changes in the receptors' conformation, a credible structure of an activated state is essential for the design of drug-like agonists. This seems to have been achieved for NTS1, as judged on the basis of previous biochemical studies and plausible comparisons with other activated GPCRs. However, a touch of ambiguity in the NTS1 structure is the poor resolution of the carboxy-terminal end of the bound peptide, which is precisely the part of the agonist that seems to be most important for activation of the receptor.
How does neurotensin turn its receptor on? The authors observe several intriguing interactions between amino-acid residues at the receptor's cytoplasmic face; such interactions might have a role in the activation mechanism. This hypothesis can now be tested straightforwardly by altering those residues by making specific mutations in the NTS1-encoding gene. Although the structure clearly shows how NTS1 binds to the peptide on the receptor's extracellular side, how this is translated into the observed active-like conformation at the cytoplasmic face is less clear. It is possible that neurotensin pulls on certain residues on NTS1 (such as arginine 327, see Fig. 1), as happens during the activation of another GPCR, the β2-adrenergic receptor7,8,9,10,11. However, the full details of NTS1 activation might be revealed only by a direct comparison of White and colleagues' structure with an inactive-like state — for example, that of NTS1 in complex with an antagonist, a molecule that locks the receptor into an inactive conformation. The structure of such an inactive state is now eagerly awaited.
In summary, the presented NTS1 structure gives an immediate guideline for the design of improved agonists. The neurotensin analogue binds in a concave pocket and establishes mainly hydrophobic contacts with the receptor, rather than extensive hydrogen bonds or electrostatic interactions — characteristics that drug discoverers like to see. If this knowledge can indeed be translated into potent NTS1 agonists (ideally, small non-peptide molecules), White and colleagues' work could be the beginning of the end for the 'poor druggability' mantra commonly associated with peptide-interacting GPCRs. And, because of neurotensin's role as a neurotransmitter in the brain, it might eventually lead to new treatment options for mental disorders such as schizophrenia1.
*This article and the paper under discussion2 were published online on 10 October 2012.
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Angewandte Chemie International Edition (2013)
Strukturen der G-Protein-gekoppelten Rezeptoren der Klasse B: Perspektiven für die Arzneimittelforschung
Angewandte Chemie (2013)
Angewandte Chemie International Edition (2012)
Angewandte Chemie (2012)