Dino Moras

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Dino Moras, born on 23 November 1944, is a French biochemist, research director at the CNRS and co-director of the Institute of Genetics and Molecular and Cellular Biology (IGBMC) [1] in Illkirch-Graffenstaden until 2010. [2]

Contents

Biography

Dino Moras is a chemist by training with a thesis defended in 1971 at the University of Strasbourg, formerly Louis-Pasteur University. After a post-doctoral fellowship at Purdue University in Indiana, USA, he joined the CNRS in 1969 and founded the department of crystallography at IBMC in 1980. In 1995 he moved with his CNRS unit in the new IGBMC. He became a member of the American Academy of Arts and Sciences in 1998 and a full member of the Academy of Sciences in 1999. [3]

In 2002, following Pierre Chambon and Jean-Louis Mandel, he was Deputy Director and then Director of the IGBMC in Strasbourg from 2002 to 2010.

Main Scientific contributions

Chemistry

1968 - Synthesis and structure determination of a heterocycle without carbon atom. [4]

1971 - Structure determination of heterocyclic cryptates. [5]

1982 - First structural characterization and imaging of H3O+, the catalytic intermediate at the heart of acid-base catalysis postulated by Brönsted in 1918). [6]

Structural Biology

Structure-function relationships in transfer RNAs (tRNAs) and aminoacyl-tRNA synthetases and their relation to the origin of the genetic code

(i) Crystal structure of tRNAasp, the second to be solved at atomic resolution. [7]

(ii) Partition of aaRSs into two classes based on structural and functional correlation (each class of enzymes targets different chiral centers). [8]

(iii) The first structure determination of a class II tRNA-aaRS complex [9] led to the elucidation of the reaction mechanism for the aspartic acid system, prototypic of all class II enzymes. It provided the structural explanation for the different chirality of the targets in the two classes. Further the crystal structure led to the discovery and functional characterization of a novel conformation of adenosine triphosphate (ATP). [10] The latter was so far only found in class II enzymes.

(iv) The crystal structure of threonyl-tRNA synthetase enlightened the molecular mechanism of the editing reaction to correct for tRNA mischarging by serine thus solving the related Pauling paradox for the fidelity of translation. [11] [12]

Transcription regulation by Nuclear Hormones Receptors (NRs)

The superfamily of NRs, ligand-dependent transcription factors, regulates the expression of important target genes. NRs control most physiological functions and are implicated in several pathological processes.

In 1995 he solved the first crystal structures of the ligand binding domains (LBDs) of two NRs of retinoids (RXR and RAR) in their apo and liganded form respectively. [13] [14] These structures allowed to define a canonical unique fold for the whole family and revealed the molecular mechanism of ligand dependent activation, setting up the bases for the design of agonist and antagonist drugs. The crystal structure of RXR LBD was the first determination of a protein structure using Xenon as heavy atom derivative.

His team contributed several other molecular structures of NRs LBDs, notably those of human VDR (vitamin D) and insect's receptor Ecdysone (EcR). [15] [16]

In 2004 a comparative analysis of the primary sequences lead to the partition of the superfamily into two classes according to mutually exclusive invariant aminoacids. A functional correlation with clear evolutionary implications could be made with their dimerization properties. Class I receptors encompasses homodimers or monomers while class II assembles the receptors that form heterodimers with RXR. [17]

In order to decipher the structural bases of the communication between nuclear receptors, DNA and components of the basal transcription machinery he used the multi-scale approach of integrative structural biology. The solution structures of several nuclear receptors heterodimers bound to their DNA response elements was the first milestone. [18] It was followed by the cryo-EM structure determination of two additional complexes. [19] [20]

Honors and awards

- Bronze Medal, CNRS, 1972, silver Medal, 1982

- French Academy of Sciences, 1987

- European Molecular Biology Organization (EMBO) member, 1987

- Academia Europaea, member, 1998

- American Academy of Arts and Sciences, member, 1998

- Chevalier de l'ordre de la Légion d'honneur, 2002

- Officier dans l’Ordre National du Mérite, 2014

Related Research Articles

<span class="mw-page-title-main">Peroxisome proliferator-activated receptor</span> Group of nuclear receptor proteins

In the field of molecular biology, the peroxisome proliferator–activated receptors (PPARs) are a group of nuclear receptor proteins that function as transcription factors regulating the expression of genes. PPARs play essential roles in the regulation of cellular differentiation, development, and metabolism, and tumorigenesis of higher organisms.

Steroid hormone receptors are found in the nucleus, cytosol, and also on the plasma membrane of target cells. They are generally intracellular receptors and initiate signal transduction for steroid hormones which lead to changes in gene expression over a time period of hours to days. The best studied steroid hormone receptors are members of the nuclear receptor subfamily 3 (NR3) that include receptors for estrogen and 3-ketosteroids. In addition to nuclear receptors, several G protein-coupled receptors and ion channels act as cell surface receptors for certain steroid hormones.

The thyroid hormone receptor (TR) is a type of nuclear receptor that is activated by binding thyroid hormone. TRs act as transcription factors, ultimately affecting the regulation of gene transcription and translation. These receptors also have non-genomic effects that lead to second messenger activation, and corresponding cellular response.

The retinoic acid receptor (RAR) is a type of nuclear receptor which can also act as a ligand-activated transcription factor that is activated by both all-trans retinoic acid and 9-cis retinoic acid, retinoid active derivatives of Vitamin A. They are typically found within the nucleus. There are three retinoic acid receptors (RAR), RAR-alpha, RAR-beta, and RAR-gamma, encoded by the RARA, RARB, RARG genes, respectively. Within each RAR subtype there are various isoforms differing in their N-terminal region A. Multiple splice variants have been identified in human RARs: four for RARA, five for RARB, and two for RARG. As with other type II nuclear receptors, RAR heterodimerizes with RXR and in the absence of ligand, the RAR/RXR dimer binds to hormone response elements known as retinoic acid response elements (RAREs) complexed with corepressor protein. Binding of agonist ligands to RAR results in dissociation of corepressor and recruitment of coactivator protein that, in turn, promotes transcription of the downstream target gene into mRNA and eventually protein. In addition, the expression of RAR genes is under epigenetic regulation by promoter methylation. Both the length and magnitude of the retinoid response is dependent of the degradation of RARs and RXRs through the ubiquitin-proteasome. This degradation can lead to elongation of the DNA transcription through disruption of the initiation complex or to end the response to facilitate further transcriptional programs. Due to RAR/RXR heterodimers acting as subtrates to the non steroid hormone ligand retinoid they are extensively involved in cell differentiation, proliferation, and apoptosis.

The retinoid X receptor (RXR) is a type of nuclear receptor that is activated by 9-cis retinoic acid, which is discussed controversially to be of endogenous relevance, and 9-cis-13,14-dihydroretinoic acid, which is likely to be the major endogenous mammalian RXR-selective agonist.

<span class="mw-page-title-main">Liver X receptor</span> Nuclear receptor

The liver X receptor (LXR) is a member of the nuclear receptor family of transcription factors and is closely related to nuclear receptors such as the PPARs, FXR and RXR. Liver X receptors (LXRs) are important regulators of cholesterol, fatty acid, and glucose homeostasis. LXRs were earlier classified as orphan nuclear receptors, however, upon discovery of endogenous oxysterols as ligands they were subsequently deorphanized.

<span class="mw-page-title-main">Pregnane X receptor</span> Mammalian protein found in Homo sapiens

In the field of molecular biology, the pregnane X receptor (PXR), also known as the steroid and xenobiotic sensing nuclear receptor (SXR) or nuclear receptor subfamily 1, group I, member 2 (NR1I2) is a protein that in humans is encoded by the NR1I2 gene.

<span class="mw-page-title-main">Nuclear receptor</span> Protein

In the field of molecular biology, nuclear receptors are a class of proteins responsible for sensing steroids, thyroid hormones, vitamins, and certain other molecules. These intracellular receptors work with other proteins to regulate the expression of specific genes thereby controlling the development, homeostasis, and metabolism of the organism.

<span class="mw-page-title-main">Nuclear receptor 4A1</span> Mammalian protein found in Homo sapiens

The nuclear receptor 4A1 also known as Nur77, TR3, and NGFI-B is a protein that in humans is encoded by the NR4A1 gene.

<span class="mw-page-title-main">Small heterodimer partner</span> Protein-coding gene in the species Homo sapiens

The small heterodimer partner (SHP) also known as NR0B2 is a protein that in humans is encoded by the NR0B2 gene. SHP is a member of the nuclear receptor family of intracellular transcription factors. SHP is unusual for a nuclear receptor in that it lacks a DNA binding domain. Therefore, it is technically neither a transcription factor nor nuclear receptor but nevertheless it is still classified as such due to relatively high sequence homology with other nuclear receptor family members.

<span class="mw-page-title-main">Retinoid X receptor alpha</span> Protein-coding gene in the species Homo sapiens

Retinoid X receptor alpha (RXR-alpha), also known as NR2B1 is a nuclear receptor that in humans is encoded by the RXRA gene.

<span class="mw-page-title-main">Retinoic acid receptor alpha</span> Protein-coding gene in the species Homo sapiens

Retinoic acid receptor alpha (RAR-α), also known as NR1B1 is a nuclear receptor that in humans is encoded by the RARA gene.

Tyrosine—tRNA ligase, also known as tyrosyl-tRNA synthetase is an enzyme that is encoded by the gene YARS. Tyrosine—tRNA ligase catalyzes the chemical reaction

<span class="mw-page-title-main">Retinoid X receptor beta</span> Protein-coding gene in the species Homo sapiens

Retinoid X receptor beta (RXR-beta), also known as NR2B2 is a nuclear receptor that in humans is encoded by the RXRB gene.

<span class="mw-page-title-main">Retinoic acid receptor gamma</span> Protein-coding gene in the species Homo sapiens

Retinoic acid receptor gamma (RAR-γ), also known as NR1B3 is a nuclear receptor encoded by the RARG gene. Adapalene selectively targets retinoic acid receptor beta and retinoic acid receptor gamma and its agonism of the gamma subtype is largely responsible for adapalene's observed effects.

<span class="mw-page-title-main">Liver X receptor beta</span> Protein-coding gene in the species Homo sapiens

Liver X receptor beta (LXR-β) is a member of the nuclear receptor family of transcription factors. LXR-β is encoded by the NR1H2 gene.

<span class="mw-page-title-main">BRD8</span> Protein-coding gene in the species Homo sapiens

Bromodomain-containing protein 8 is a protein that in humans is encoded by the BRD8 gene.

<span class="mw-page-title-main">POLR1B</span> Protein-coding gene in the species Homo sapiens

DNA-directed RNA polymerase I subunit RPA2 is an enzyme that in humans is encoded by the POLR1B gene.

<span class="mw-page-title-main">Ecdysone receptor</span>

The ecdysone receptor is a nuclear receptor found in arthropods, where it controls development and contributes to other processes such as reproduction. The receptor is a non-covalent heterodimer of two proteins, the EcR protein and ultraspiracle protein (USP). It binds to and is activated by ecdysteroids. Insect ecdysone receptors are currently better characterized than those from other arthropods, and mimics of ecdysteroids are used commercially as caterpillar-selective insecticides.

<span class="mw-page-title-main">Stephen A. Cusack</span>

Stephen Anthony Cusack FRS is the former Head of the European Molecular Biology Laboratory (EMBL) site in Grenoble, France.

References

  1. ↑ "Équipe Biologie structurale intégrative". Institut de génétique et de biologie moléculaire et cellulaire. Archived from the original on 12 April 2019. Retrieved 12 April 2019.
  2. ↑ Académie des sciences : Dino Moras Archived 2014-02-28 at the Wayback Machine , CV sur le site de l'Académie des sciences  : www.academie-sciences.fr. Accessed 14 Feb 2013
  3. ↑ Académie des sciences. "Présentation de Dino Moras". www.academie-sciences.fr (in French). Archived from the original on 21 February 2014. Retrieved 18 February 2014.
  4. ↑ Moras, D. (1968). "Crystal structure of di-(phosporyl trichloride) hexachloroditin (IV) di- u dichlorophosphate". Chem. Comm. 26.
  5. ↑ Metz, B. (1970). "Crystal structure of a rubidium "cryptate"". Chem. Comm. 217.
  6. ↑ Behr, J.P. (1982). "The H30+cation: molecular structure of an oxonium-macrocyclic polyether complex". J. Am. Chem. Soc. 104: 4540–4543. doi:10.1021/ja00381a007.
  7. ↑ Moras D. (1980). "3D structure of yeast tRNAAsp". Nature. 288 (5792): 669–674. doi:10.1038/288669a0. PMID   7005687. S2CID   4366566.
  8. ↑ Eriani, G. (1990). "Partition of tRNA-synthetases into two classes based on mutually exclusive sets of sequence motifs". Nature. 347 (6289): 203–206. Bibcode:1990Natur.347..203E. doi:10.1038/347203a0. PMID   2203971. S2CID   4324290.
  9. ↑ Ruff, M. (1991). "Class II aminoacyl tRNA-synthetases : crystal structure of yeast aspartyl-tRNA synthetase complexed with tRNAAsp". Science. 252 (5013): 1682–1689. doi:10.1126/science.2047877. PMID   2047877. S2CID   27787794.
  10. ↑ Cavarelli, J. (1994). "The active site of yeast aspartyl-tRNA synthetase: structural and functional aspects of the aminoacylation reaction". EMBO J. 113 (2): 327–37. doi:10.1002/j.1460-2075.1994.tb06265.x. PMC   394812 . PMID   8313877.
  11. ↑ Sankaranarayanan, R. (1999). "The structure of threonyl-tRNA synthetase-tRNA(Thr) complex enlightens its repressor activity and reveals an essential zinc ion in the active site". Cell. 97 (3): 371–381. doi: 10.1016/S0092-8674(00)80746-1 . PMID   10319817. S2CID   1019704.
  12. ↑ Dock-Bregeon, A-C. (2000). "Transfer RNA-Mediated editing in threonyl-tRNA synthetase : The class II solution to the double discrimination problem". Cell. 103 (6): 877–884. doi: 10.1016/S0092-8674(00)00191-4 . PMID   11136973. S2CID   881672.
  13. ↑ Bourguet, William; Ruff, Marc; Chambon, Pierre; Gronemeyer, Hinrich; Moras, Dino (June 1995). "Crystal structure of the ligand-binding domain of the human nuclear receptor RXR-α". Nature. 375 (6530): 377–382. Bibcode:1995Natur.375..377B. doi:10.1038/375377a0. PMID   7760929. S2CID   4371873.
  14. ↑ Renaud, Jean-Paul; Rochel, Natacha; Ruff, Marc; Vivat, Valéria; Chambon, Pierre; Gronemeyer, Hinrich; Moras, Dino (December 1995). "Crystal structure of the RAR-γ ligand-binding domain bound to all-trans retinoic acid". Nature. 378 (6558): 681–689. Bibcode:1995Natur.378..681R. doi:10.1038/378681a0. PMID   7501014. S2CID   4259376.
  15. ↑ Rochel, N. (2000). "The crystal structure of the nuclear receptor for vitamin D bound to its natural ligand". Mol Cell. 5 (1): 173–179. doi: 10.1016/S1097-2765(00)80413-X . PMID   10678179.
  16. ↑ Billas, Isabelle M. L.; Iwema, Thomas; Garnier, Jean-Marie; Mitschler, André; Rochel, Natacha; Moras, Dino (2 November 2003). "Structural adaptability in the ligand-binding pocket of the ecdysone hormone receptor". Nature. 426 (6962): 91–96. Bibcode:2003Natur.426...91B. doi:10.1038/nature02112. PMID   14595375. S2CID   4413300.
  17. ↑ Brelivet, Yann; Kammerer, Sabrina; Rochel, Natacha; Poch, Olivier; Moras, Dino (April 2004). "Signature of the oligomeric behaviour of nuclear receptors at the sequence and structural level". EMBO Reports. 5 (4): 423–429. doi:10.1038/sj.embor.7400119. PMC   1299030 . PMID   15105832.
  18. ↑ Rochel, Natacha; Ciesielski, Fabrice; Godet, Julien; Moman, Edelmiro; Roessle, Manfred; Peluso-Iltis, Carole; Moulin, Martine; Haertlein, Michael; Callow, Phil; Mély, Yves; Svergun, Dmitri I; Moras, Dino (10 April 2011). "Common architecture of nuclear receptor heterodimers on DNA direct repeat elements with different spacings". Nature Structural & Molecular Biology. 18 (5): 564–570. doi:10.1038/nsmb.2054. PMID   21478865. S2CID   2700061.
  19. ↑ Orlov, Igor; Rochel, Natacha; Moras, Dino; Klaholz, Bruno P (18 January 2012). "Structure of the full human RXR/VDR nuclear receptor heterodimer complex with its DR3 target DNA". The EMBO Journal. 31 (2): 291–300. doi:10.1038/emboj.2011.445. PMC   3261568 . PMID   22179700.
  20. ↑ Maletta, Massimiliano; Orlov, Igor; Roblin, Pierre; Beck, Yannick; Moras, Dino; Billas, Isabelle M. L.; Klaholz, Bruno P. (19 June 2014). "The palindromic DNA-bound USP/EcR nuclear receptor adopts an asymmetric organization with allosteric domain positioning". Nature Communications. 5 (1): 4139. Bibcode:2014NatCo...5.4139M. doi: 10.1038/ncomms5139 . PMID   24942373.
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