- Vanderbilt article highlighting JCI paper.
- Ray PI on Vanderbilt Trans-Institutional Program Award.
- Materials & Methods Blog post, "Why Study That".
Independent Lab (Blind Lab members underlined):
24. Lipid regulation of full-length nuclear receptor structure.
*Haratipour Z, *Choi HS, Blind RD.
In Revision J. Lipid Res. 2023
23. A new high-throughput screen discovers novel ligands of full-length nuclear receptor LRH-1.
Malabanan MM, Chapagain P, Haratipour Z, Choi WJ, Orun AR, Blind RD.
Accepted at ACS Chemical Biology 2023
Develops a new high-throughput screen for nuclear receptor LRH-1, using only commercially available reagents. The screen discovered several new ligands for LRH-1, one of these was Abamectin, which is proposed to regulate LRH-1 through a new mechanism.
22. The acyl chains of phosphoinositide PIP3 alter the structure and function of nuclear receptor Steroidogenic Factor-1 (NR5A1).
Bryant JM, Malabanan MM, Vanderloop BH, Nichols CM, Haratipour Z, Poon KT, Sherrod SD, McLean JA, Blind RD.
J Lipid Res. 2021 Apr 29:100081
PMID: 33933440 PDF
First data showing phosphoinositide acyl chains regulate the structure and function of nuclear receptor SF-1 (NR5A1). The data show how the acyl chains regulate SF-1 function in vitro, improving our understanding of how lipids can regulate gene expression in vivo, particularly in the adrenals, gonads & ventral medial hypothalamus.
21. Integrated structural modeling of full-length LRH-1 reveals inter-domain interactions contribute to receptor structure and function.
Seacrist CD, Kuenze G, Hoffmann RM, Moeller BE, Burke JE, Meiler J, Blind RD.
Structure. 2020 May 19:S0969-2126(20)30166-0. doi: 10.1016/j.str.2020.04.020.
First structure of a full-length monomeric nuclear receptor, LRH-1, which is an important target for Diabetes & NASH. The structure unifies unexplained mutations and human polymorphisms that affect LRH-1 function, providing new therapeutic strategies for Type 2 Diabetes, NAFLD and NASH.
20. Structural analyses of inositol phosphate second messengers bound to signaling effector proteins.
Adv Biol Regul. 2020 Jan;75:100667. doi: 10.1016/j.jbior.2019.100667. Epub 2019 Oct 11.
Used the protein structure database (PDB) to identify structural motifs common to proteins known to interact with inositide signaling molecules.
19. Human islets expressing HNF1A variant have defective β cell transcriptional regulatory networks.
Haliyur R, Tong X, Sanyoura M, Shrestha S, Lindner J, Saunders DC, Aramandla R, Poffenberger G, Redick SD, Bottino R, Prasad N, Levy SE, Blind RD, Harlan DM, Philipson LH, Stein RW, Brissova M, Powers AC.
J Clin Invest. 2019 Jan 2;129(1):246-251. doi: 10.1172/JCI121994. Epub 2018 Dec 3.
Defines the molecular basis of clinically-relevant pathological human mutations in the nuclear receptor HNF1A.
18. Signaling through non-membrane nuclear phosphoinositide binding proteins in human health and disease.
Bryant JM, Blind RD.
J Lipid Res. 2019 Feb;60(2):299-311. doi: 10.1194/jlr.R088518. Epub 2018 Sep 10.
17. Crystallographic and kinetic analyses of human IPMK reveal disordered domains modulate ATP binding and kinase activity.
Seacrist CD, Blind RD.
Sci Rep. 2018 Nov 12;8(1):16672. doi: 10.1038/s41598-018-34941-3.
Crystal structure and functional analyses of human IPMK, an important target in glioblastoma, showing how IPMK disordered domains auto-inhibit its own kinase activity. The data reveal new ways IPMK is regulated and introduce new inhibitor strategies.
16. Nuclear phosphoinositide regulation of chromatin.
Hamann BL, Blind RD.
J Cell Physiol. 2018 Jan;233(1):107-123. doi: 10.1002/jcp.25886. Epub 2017 May 3.
15. Phospholipid regulation of the nuclear receptor superfamily.
Crowder MK, Seacrist CD, Blind RD.
Adv Biol Regul. 2017 Jan;63:6-14. doi: 10.1016/j.jbior.2016.10.006. Epub 2016 Oct 29.
14. Inositol polyphosphate multikinase (IPMK) in transcriptional regulation and nuclear inositide metabolism.
Malabanan MM, Blind RD.
Biochem Soc Trans. 2016 Feb;44(1):279-85. doi: 10.1042/BST20150225.
Postdoc and PhD:
13. Structure of Liver Receptor Homolog-1 (NR5A2) with PIP3 hormone bound in the ligand binding pocket.
*Sablin EP, *Blind RD, Uthayaruban R, Chiu HJ, Deacon AM, Das D, Ingraham HA, Fletterick RJ.
J Struct Biol. 2015 Dec;192(3):342-348. doi: 10.1016/j.jsb.2015.09.012. Epub 2015 Sep 28.
First structure of the nuclear receptor LRH-1 bound to an endogenous mammalian ligand.
12. The signaling phospholipid PIP3 creates a new interaction surface on the nuclear receptor SF-1.
Blind RD, Sablin EP, Kuchenbecker KM, Chiu HJ, Deacon AM, Das D, Fletterick RJ, Ingraham HA.
Used structural biology to show the nuclear receptor SF-1 does not change shape dependent on the PIP3 headgroup, thus this transcription factor is likely regulated through a mechanism distinct from other nuclear receptors.
11. Disentangling biological signaling networks by dynamic coupling of signaling lipids to modifying enzymes.
Adv Biol Regul. 2014 Jan;54:25-38. doi: 10.1016/j.jbior.2013.09.015. Epub 2013 Oct 18.
10. Direct modification and activation of a nuclear receptor-PIP2 complex by the inositol lipid kinase IPMK.
Blind RD, Suzawa M, Ingraham HA.
Sci Signal. 2012 Jun 19;5(229):ra44. doi: 10.1126/scisignal.2003111.
(Featured on Cover) - This paper showed signaling enzymes (IPMK and PTEN) can remodel a second-messenger signaling molecule (the PIP2 lipid) while that second messenger is bound to a protein effector (the nuclear receptor SF-1). This paper was the first to show:
1) Nuclear lipid signaling enzymes act directly on non-membrane nuclear phosphoinositides,
2) A specific function for nuclear phosphoinositides,
3) A mechanism nuclear phosphoinositides use to modulate gene expression,
4) Signaling enzymes can modify second messengers bound to an effector protein,
5) Signaling enzymes can operate with unique enzyme kinetics on second messengers bound bound to effector proteins.
10a. Science Signaling Podcast: 19 June 2012.
Ingraham HA, Blind RD, VanHook AM.
Science Signaling 2012 Jun; 5(229): pc13 [DOI: 10.1126/scisignal.2003287]: Podcast
9. Ligand structural motifs can decouple glucocorticoid receptor transcriptional activation from target promoter occupancy.
Blind RD, Pineda-Torra I, Xu Y, Xu HE, Garabedian MJ.
Shows nuclear receptor ligands can induce receptor recruitment to promoters, but fail to activate transcription. SAR to induce this dominant-negative activity could decrease side effects of nuclear receptor partial agonists.
8. Small molecule agonists of the orphan nuclear receptors steroidogenic factor-1 (SF-1, NR5A1) and liver receptor homologue-1 (LRH-1, NR5A2).
Whitby RJ, Stec J, Blind RD, Dixon S, Leesnitzer LM, Orband-Miller LA, Williams SP, Willson TM, Xu R, Zuercher WJ, Cai F, Ingraham HA.
J Med Chem. 2011 Apr 14;54(7):2266-81. doi: 10.1021/jm1014296. Epub 2011 Mar 10.
Developed novel chemical antagonists of SF-1 and LRH-1 phospholipid binding.
7. Regulation of C. elegans fat uptake and storage by acyl-CoA synthase-3 is dependent on NR5A family nuclear hormone receptor nhr-25.
Mullaney BC, Blind RD, Lemieux GA, Perez CL, Elle IC, Faergeman NJ, Van Gilst MR, Ingraham HA, Ashrafi K.
Cell Metab. 2010 Oct 6;12(4):398-410. doi: 10.1016/j.cmet.2010.08.013.
Functionally and biochemically links NR5A with phospholipid metabolism in worms.
6. Stimulating the GPR30 estrogen receptor with a novel tamoxifen analogue activates SF-1 and promotes endometrial cell proliferation.
*Lin BC, *Suzawa M, *Blind RD, Tobias SC, Bulun SE, Scanlan TS, Ingraham HA.
Cancer Res. 2009 Jul 1;69(13):5415-23. doi: 10.1158/0008-5472.CAN-08-1622. Epub 2009 Jun 23.
Shows estrogen activation of a plasma membrane receptor (GPR30) induces intracellular production of PIP3, which activates a nuclear receptor (NR5A1, SF-1). This represents one of the clearest examples of GPCR-nuclear receptor cross-talk.
5. Structure of SF-1 bound by different phospholipids: evidence for regulatory ligands.
*Sablin EP, *Blind RD, Krylova IN, Ingraham JG, Cai F, Williams JD, Fletterick RJ, Ingraham HA.
Mol Endocrinol. 2009 Jan;23(1):25-34. doi: 10.1210/me.2007-0508. Epub 2008 Nov 6.
First crystal structure of an NR5A nuclear receptor bound to an endogenous mammalian phospholipid.
4. Applying innovative educational principles when classes grow and resources are limited: Biochemistry experiences at Muhimbili University of Allied Health Sciences.
Omer S, Hickson G, Taché S, Blind R, Masters S, Loeser H, Souza K, Mkony C, Debas H, O'Sullivan P.
Biochem Mol Biol Educ. 2008 Nov;36(6):387-94. doi: 10.1002/bmb.20210.
3. Glucocorticoid receptor phosphorylation differentially affects target gene expression.
*Chen W, *Dang T, *Blind RD, Wang Z, Cavasotto CN, Hittelman AB, Rogatsky I, Logan SK, Garabedian MJ.
Mol Endocrinol. 2008 Aug;22(8):1754-66. doi: 10.1210/me.2007-0219. Epub 2008 May 15.
2. Differential recruitment of glucocorticoid receptor phospho-isoforms to glucocorticoid-induced genes.
Blind RD, Garabedian MJ.
1. Stabilization of the unliganded glucocorticoid receptor by TSG101.
Ismaili N, Blind R, Garabedian MJ.
J Biol Chem. 2005 Mar 25;280(12):11120-6. doi: 10.1074/jbc.M500059200. Epub 2005 Jan 18.