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Wordle of IPMK, SF-1, PIP3, PIP2 and PTEN for Ray Blind Vanderbilt University
Press Highlights:
     - Vanderbilt article highlighting JCI paper.
     - Ray wins Journal of Lipid Research Junior investigator Award.
     - Ray PI on Vanderbilt Trans-Institutional Program Award.
     - ASBMB Today Lipid News Article.
     - Ray interviewed by American Cancer Society Relay for Life.
     - Ray on an ESPN commercial for Jimmy V-week at 13:20.
     - Ray awarded Jimmy-V Foundation for Cancer Research V-Scholar Award.
     - Ray wins a JBC / Herb Tabor Young Investigator Award.
     - Structural Biology Knowledge Database Featured Article.
     - SLAC National Accelerator Lab News Feature Article.
     - Research Media Focus on Cancer.
     - Materials & Methods Blog post, "Why Study That"

Independent Lab  (Blind Lab members underlined):
2024:

35. PI5P links the Hippo Pathway and PI5P4K signaling.

Palamiuc L, Johnson JL, Choi WJ, Haratipour Z, Arora GK, Tieu V, Loughran R, Rameh LE, Wong J,

Blind RD*, Emerling BM*.

*Co-Corresponding, 

Accepted at Science Signaling on May 9, 2024,   Cover Image!

PMID: 38805583

Discovery of a novel PI5P-receptor that links the Hippo Pathway to phosphoinositide signaling, validating PI5P4K as a target in several Hippo-dependent cancers.

         * Focus Commentary by Emilio Hirsch, et. al. Sci Signaling doi:10.1126/scisignal.adp3504

34. Bilirubin is a ligand for nuclear receptor Liver Receptor Homolog-1.

Chapagain P, Orun AR, Haratiopur Z, Malabanan MM, Blind RD.

bioRxiv, 2024   doi.org/10.1101/2024.05.05.592606

PMID: 38853895

Discovered and validated bilirubin as a new regulatory hormone that activates the liver nuclear receptor LRH-1.

33. A novel heuristic of docked ligand binding energy associates with functional regulation of full length nuclear receptor LRH-1.

Haratiopur Z, Foutch D, Blind RD.

bioRxiv 2024,  doi.org/10.1101/2024.05.05.592617

Novel computational approach to predict compound activation of nuclear receptor LRH-1.

Papers 32 and 31 below had to be separated into two separate manuscripts due to a recent dispute between authors (April 2024) that had nothing to do with any members of the Blind Lab, note Ray and other members of the Blind lab are still authors on both manuscripts: 

32. X-ray crystallographic analyses of 14 new IPMK inhibitor complexes.  

Wang H*, Blind RD*, Shears SB*, 

*Co-corresponding authors.

bioRxiv, 2024   doi.org/10.1101/2024.05.09.593385

PMID: 38766172

A total of 14 new co-crystal structures of IPMK with 1st and 2nd generation IPMK chemical inhibitors reveals new ordered water molecules and clefts within IPMK that will aid optimization of pharmacokinetic properties of IPMK glioblastoma drugs currently under development.

31. Design, synthesis and cellular characterization of a new class of IPMK inhibitors.

Zhou Y*, Chapagain P*, Desmarini D, Uredi D, Rameh, LE, Djordjevic JT, Blind RD*, Wang X*

*Co-first authors.

*Co-corresponding authors.

bioRxiv 2024  doi.org/10.1101/2024.05.09.593371

PMID: 38798512 

Development, DMPK optimization and cellular validation of the first IPMK inhibitors with nano-molar potency, with clinical potential in glioblastoma.

30. Multiple inositol phosphate species enhance stability of active mTOR.

Rameh, LE*, York JD, Blind RD*

*Co-corresponding authors.

bioRxiv 2024,  doi.org/10.1101/2024.05.01.592113

PMID: 38746235 

Discovery that multiple inositol phosphate species can stabilize active mTOR by directly binding the catalytic domain of mTORC1 (mTOR).

29. IPMK activates HDAC3 and regulates histone acetylation in human cells.

Sowd GA, Stivison EA, Chapagain P, Haratipour Z, Hale A, Rameh LE, Blind RD.

Under review, Science Signaling  doi.org/10.1101/2024.04.29.591660

PMID: 38746349

28. Biochemical and Metabolic Characterization of a G6PC2 Inhibitor.

Hawes EM, Rahim M, Haratipour Z, Orun AR, O'Rourke ML, Oeser JK, Kim K, Claxton DP, Blind RD, Young JD, O'Brien RM.

Biochimie. 2024 Mar 1;222:109-122. doi: 10.1016/j.biochi.2024.02.012.

PMID: 38431189

Inhibitor binding studies confirm computational docking that reveals multiple novel regulatory binding sites for new inhibitors of Glucose-6-Phosphatase.

 

27. Steroidogenic Factor-1 form and function: From phospholipids to physiology.

*Campbell AN, *Choi WJ, *Chi ES, *Orun AR, *Poland JC, *Stivison EA, Kubina JN, Hudson KL, Loi MNC, Bhatia JN, Gilligan JW, Quintanà AA, Blind RD.

Adv Biol Regul. 2024 Jan 100991. doi: 10.1016/j.jbior.2023.100991. 

PMID: 37802761   PDF

2023:

26. SF-1 Induces Nuclear PIP2.

Chi ES, Stivison EA, Blind RD.

Biomolecules. 2023 Oct 12;13(10):1509. doi: 10.3390/biom13101509.

PMID: 37892191   PDF

Demonstrates that nuclear receptor SF-1 co-localizes with nuclear PIP2 in human cells, dependent on the ability of SF-1 to bind PIP2. First study to demonstrate SF-1 associates with PIP2 in intact cells. 

25. 25 Years of PI5P.

Rameh LE, Blind RD.

Front Cell Dev Biol. 2023 Oct 2;11:1272911. doi: 10.3389/fcell.2023.1272911. 

PMID: 37849742   PDF

Review of the past 25 years of researching to the in low abundance lipid PI5P.

24. Fulll-length nuclear receptor allosteric regulation.

*Choi HS*Haratipour Z, Blind RD.

J Lipid Res. 2023 Aug;64(8):100406. doi: 10.1016/j.jlr.2023.100406. Epub 2023 Jun 24.

PMID: 37356665   PDF

Comprehensive review of how lipids regulate full-length nuclear receptor structure.

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.

ACS Chem Biol. 2023 May 19;18(5):1101-1114. doi: 10.1021/acschembio.2c00805.

PMID: 37074920   PDF

Developed a new high-throughput screen for nuclear receptor drug screening against LRH-1. The screen discovered several new ligands for LRH-1, one of these was Abamectin, is proposed to regulate LRH-1 through a novel molecular mechanism.

2021:

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.

2020:

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.   

PMID: 32433991   PDF

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.

Blind RD.

Adv Biol Regul. 2020 Jan;75:100667. doi: 10.1016/j.jbior.2019.100667. Epub 2019 Oct 11.

PMID: 31648945  PDF

Used the protein structure database (PDB) to identify structural motifs common to proteins known to interact with inositide signaling molecules.

2019:

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. 

PMID: 30507613     PDF

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. 

PMID: 30201631     PDF

2018:

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. 

PMID: 30420721     PDF

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

PMID: 28256711    PDF

2017:

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. 

PMID: 27838257     PDF

2016:

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. 

PMID: 26862216    PDF

Postdoc and PhD:

2015:

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. 

PMID: 26416531    PDF

First structure of the nuclear receptor LRH-1 bound to an endogenous mammalian ligand.

2014:

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.

Proc Natl Acad Sci U S A. 2014 Oct 21;111(42):15054-9. doi: 10.1073/pnas.1416740111. Epub 2014 Oct 6.  PMID: 25288771     PDF

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.

2013:

11. Disentangling biological signaling networks by dynamic coupling of signaling lipids to modifying enzymes.

Blind RD.

Adv Biol Regul. 2014 Jan;54:25-38. doi: 10.1016/j.jbior.2013.09.015. Epub 2013 Oct 18. 

PMID: 24176936     PDF

 

2012:

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. 

PMID: 22715467     PDF

(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.

Biochem Biophys Res Commun. 2012 Apr 20;420(4):839-44. doi: 10.1016/j.bbrc.2012.03.084. Epub 2012 Mar 23.   PMID: 22465009   PDF

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.

 

2011:

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. 

PMID: 21391689   PDF

Developed novel chemical antagonists of SF-1 and LRH-1 phospholipid binding.

 

2010:

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. 

PMID: 20889131    PDF

Functionally and biochemically links NR5A with phospholipid metabolism in worms.

 

2009:

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. 

PMID: 19549922    PDF

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. 

PMID: 18988706    PDF

First crystal structure of an NR5A nuclear receptor bound to an endogenous mammalian phospholipid.

 

2008:

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. 

PMID: 21591227   PDF

 

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. 

PMID: 18483179    PDF

 

2.    Differential recruitment of glucocorticoid receptor phospho-isoforms to glucocorticoid-induced genes.

Blind RD, Garabedian MJ.

J Steroid Biochem Mol Biol. 2008 Mar;109(1-2):150-7. doi: 10.1016/j.jsbmb.2008.01.002. Epub 2008 Jan 19.  PMID: 18304804    PDF

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. 

PMID: 15657031   PDF

All Publications:  

PubMed icon linke to all publications of the Blind Lab and Ray Blind Vanderbilt University
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Science Signaling Cover image for June 19, 2012, showing Nuclear Lipid Signaling through SF-1 bound to PIP2.  Image is a simulation, not a crystal structure.
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