5kw2

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The extra-helical binding site of GPR40 and the structural basis for allosteric agonism and incretin stimulation

Structural highlights

5kw2 is a 1 chain structure with sequence from Escherichia virus T4 and Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.76Å
Ligands:6XQ
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

ENLYS_BPT4 Endolysin with lysozyme activity that degrades host peptidoglycans and participates with the holin and spanin proteins in the sequential events which lead to the programmed host cell lysis releasing the mature viral particles. Once the holin has permeabilized the host cell membrane, the endolysin can reach the periplasm and break down the peptidoglycan layer.[1] FFAR1_HUMAN Receptor for medium and long chain saturated and unsaturated fatty acids. Binding of the ligand increase intracellular calcium concentration and amplify glucose-stimulated insulin secretion. The activity of this receptor is mediated by G-proteins that activate phospholipase C. Seems to act through a G(q) and G(i)-mediated pathway.[2]

Publication Abstract from PubMed

Activation of free fatty acid receptor 1 (GPR40) by synthetic partial and full agonists occur via distinct allosteric sites. A crystal structure of GPR40-TAK-875 complex revealed the allosteric site for the partial agonist. Here we report the 2.76-A crystal structure of human GPR40 in complex with a synthetic full agonist, compound 1, bound to the second allosteric site. Unlike TAK-875, which acts as a Galphaq-coupled partial agonist, compound 1 is a dual Galphaq and Galphas-coupled full agonist. compound 1 binds in the lipid-rich region of the receptor near intracellular loop 2 (ICL2), in which the stabilization of ICL2 by the ligand is likely the primary mechanism for the enhanced G protein activities. The endogenous free fatty acid (FFA), gamma-linolenic acid, can be computationally modeled in this site. Both gamma-linolenic acid and compound 1 exhibit positive cooperativity with TAK-875, suggesting that this site could also serve as a FFA binding site.

Structural basis for GPR40 allosteric agonism and incretin stimulation.,Ho JD, Chau B, Rodgers L, Lu F, Wilbur KL, Otto KA, Chen Y, Song M, Riley JP, Yang HC, Reynolds NA, Kahl SD, Lewis AP, Groshong C, Madsen RE, Conners K, Lineswala JP, Gheyi T, Saflor MD, Lee MR, Benach J, Baker KA, Montrose-Rafizadeh C, Genin MJ, Miller AR, Hamdouchi C Nat Commun. 2018 Apr 25;9(1):1645. doi: 10.1038/s41467-017-01240-w. PMID:29695780[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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Citations
7 reviews cite this structure
Targeting lipid GPCRs to treat type 2 diabetes mellitus - progress and challenges.
Ghislain et al. (2021)
6 more
16 other articles
No citations found

See Also

References

  1. ↑ Moussa SH, Kuznetsov V, Tran TA, Sacchettini JC, Young R. Protein determinants of phage T4 lysis inhibition. Protein Sci. 2012 Apr;21(4):571-82. doi: 10.1002/pro.2042. Epub 2012 Mar 2. PMID:22389108 doi:http://dx.doi.org/10.1002/pro.2042
  2. ↑ Briscoe CP, Tadayyon M, Andrews JL, Benson WG, Chambers JK, Eilert MM, Ellis C, Elshourbagy NA, Goetz AS, Minnick DT, Murdock PR, Sauls HR Jr, Shabon U, Spinage LD, Strum JC, Szekeres PG, Tan KB, Way JM, Ignar DM, Wilson S, Muir AI. The orphan G protein-coupled receptor GPR40 is activated by medium and long chain fatty acids. J Biol Chem. 2003 Mar 28;278(13):11303-11. Epub 2002 Dec 19. PMID:12496284 doi:http://dx.doi.org/10.1074/jbc.M211495200
  3. ↑ Ho JD, Chau B, Rodgers L, Lu F, Wilbur KL, Otto KA, Chen Y, Song M, Riley JP, Yang HC, Reynolds NA, Kahl SD, Lewis AP, Groshong C, Madsen RE, Conners K, Lineswala JP, Gheyi T, Saflor MD, Lee MR, Benach J, Baker KA, Montrose-Rafizadeh C, Genin MJ, Miller AR, Hamdouchi C. Structural basis for GPR40 allosteric agonism and incretin stimulation. Nat Commun. 2018 Apr 25;9(1):1645. doi: 10.1038/s41467-017-01240-w. PMID:29695780 doi:http://dx.doi.org/10.1038/s41467-017-01240-w

Contents


PDB ID 5kw2

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OCA

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