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. 1999 Oct;8(10):2027–2032. doi: 10.1110/ps.8.10.2027

Protein and ligand adaptation in a retinoic acid binding protein.

R Pattanayek 1, M E Newcomer 1
PMCID: PMC2144134  PMID: 10548048

Abstract

A retinoic acid binding protein isolated from the lumen of the rat epididymis (ERABP) is a member of the lipocalin superfamily. ERABP binds both the all-trans and 9-cis isomers of retinoic acid, as well as the synthetic retinoid (E)-4-[2-(5,6,7,8)-tetrahydro-5,5,8,8-tetramethyl-2 napthalenyl-1 propenyl]-benzoic acid (TTNPB), a structural analog of all-trans retinoic acid. The structure of ERABP with a mixture of all-trans and 9-cis retinoic acid has previously been reported. To elucidate any structural differences in the protein when bound to the all-trans and 9-cis isomers, the structures of all-trans retinoic acid-ERABP and 9-cis retinoic acid ERABP were determined. Our results indicate that the all-trans isomer of retinoic acid adopts an 8-cis structure in the binding cavity with no concomitant conformational change in the protein. The structure of TTNPB-ERABP is also reported herein. To accommodate this all-trans analog, which cannot readily adopt a cis-like structure, alternative positioning of critical binding site side chains is required. Consequently, both protein and ligand adaption are observed in the formation of the various holo-proteins.

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Selected References

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  1. Bourguet W., Ruff M., Chambon P., Gronemeyer H., Moras D. Crystal structure of the ligand-binding domain of the human nuclear receptor RXR-alpha. Nature. 1995 Jun 1;375(6530):377–382. doi: 10.1038/375377a0. [DOI] [PubMed] [Google Scholar]
  2. Cowan S. W., Newcomer M. E., Jones T. A. Crystallographic refinement of human serum retinol binding protein at 2A resolution. Proteins. 1990;8(1):44–61. doi: 10.1002/prot.340080108. [DOI] [PubMed] [Google Scholar]
  3. Jones T. A., Zou J. Y., Cowan S. W., Kjeldgaard M. Improved methods for building protein models in electron density maps and the location of errors in these models. Acta Crystallogr A. 1991 Mar 1;47(Pt 2):110–119. doi: 10.1107/s0108767390010224. [DOI] [PubMed] [Google Scholar]
  4. Kim K. H., Griswold M. D. The regulation of retinoic acid receptor mRNA levels during spermatogenesis. Mol Endocrinol. 1990 Nov;4(11):1679–1688. doi: 10.1210/mend-4-11-1679. [DOI] [PubMed] [Google Scholar]
  5. Klaholz B. P., Renaud J. P., Mitschler A., Zusi C., Chambon P., Gronemeyer H., Moras D. Conformational adaptation of agonists to the human nuclear receptor RAR gamma. Nat Struct Biol. 1998 Mar;5(3):199–202. doi: 10.1038/nsb0398-199. [DOI] [PubMed] [Google Scholar]
  6. Kleywegt G. J., Bergfors T., Senn H., Le Motte P., Gsell B., Shudo K., Jones T. A. Crystal structures of cellular retinoic acid binding proteins I and II in complex with all-trans-retinoic acid and a synthetic retinoid. Structure. 1994 Dec 15;2(12):1241–1258. doi: 10.1016/s0969-2126(94)00125-1. [DOI] [PubMed] [Google Scholar]
  7. Lepperdinger G., Strobl B., Jilek A., Weber A., Thalhamer J., Flöckner H., Mollay C. The lipocalin Xlcpl1 expressed in the neural plate of Xenopus laevis embryos is a secreted retinaldehyde binding protein. Protein Sci. 1996 Jul;5(7):1250–1260. doi: 10.1002/pro.5560050704. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Mangelsdorf D. J., Ong E. S., Dyck J. A., Evans R. M. Nuclear receptor that identifies a novel retinoic acid response pathway. Nature. 1990 May 17;345(6272):224–229. doi: 10.1038/345224a0. [DOI] [PubMed] [Google Scholar]
  9. Newcomer M. E., Ong D. E. Purification and crystallization of a retinoic acid-binding protein from rat epididymis. Identity with the major androgen-dependent epididymal proteins. J Biol Chem. 1990 Aug 5;265(22):12876–12879. [PubMed] [Google Scholar]
  10. Newcomer M. E., Pappas R. S., Ong D. E. X-ray crystallographic identification of a protein-binding site for both all-trans- and 9-cis-retinoic acid. Proc Natl Acad Sci U S A. 1993 Oct 1;90(19):9223–9227. doi: 10.1073/pnas.90.19.9223. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Newcomer M. E. Structure of the epididymal retinoic acid binding protein at 2.1 A resolution. Structure. 1993 Sep 15;1(1):7–18. doi: 10.1016/0969-2126(93)90004-z. [DOI] [PubMed] [Google Scholar]
  12. Renaud J. P., Rochel N., Ruff M., Vivat V., Chambon P., Gronemeyer H., Moras D. Crystal structure of the RAR-gamma ligand-binding domain bound to all-trans retinoic acid. Nature. 1995 Dec 14;378(6558):681–689. doi: 10.1038/378681a0. [DOI] [PubMed] [Google Scholar]
  13. Sundaram M., Sivaprasadarao A., Aalten D. M., Findlay J. B. Expression, characterization and engineered specificity of rat epididymal retinoic acid-binding protein. Biochem J. 1998 Aug 15;334(Pt 1):155–160. doi: 10.1042/bj3340155. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Wan Y. J., Wang L., Wu T. C. Detection of retinoic acid receptor mRNA in rat tissues by reverse transcriptase-polymerase chain reaction. J Mol Endocrinol. 1992 Dec;9(3):291–294. doi: 10.1677/jme.0.0090291. [DOI] [PubMed] [Google Scholar]
  15. Zanotti G., Berni R., Monaco H. L. Crystal structure of liganded and unliganded forms of bovine plasma retinol-binding protein. J Biol Chem. 1993 May 25;268(15):10728–10738. [PubMed] [Google Scholar]

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