The Crystal Structure of the Nuclear Receptor for Vitamin D Bound to Its Natural Ligand

Rochel, Natacha; Wurtz, Jean‐Marie; Mitschler, A.; Klaholz, Bruno P.; Moras, Dino

doi:10.1016/s1097-2765(00)80413-x

Cited by 764 publications

(825 citation statements)

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“…Like the x-ray crystal structures of VDR superagonists [14] and 1,25D [11], the recently solved KH-VDR (VDR from zebrafish) complex [12] clearly demonstrates that the ligand binding pocket adapts to the KH sterol so it stabilizes the closed VDR H12 conformation (hVDR-c1). The KH-VDR x-ray result does correlate well with its ability to transactivate with similar or greater efficacy relative to 1,25D; however, the structure does not correlate with KH's solution state PSA results or reduced VDR affinity [18].…”

Section: Introductionmentioning

confidence: 81%

“…1C, yellow circles). Residues N424, E425, I426, and S427 are unresolved in the 1,25D-VDR x-ray structures [11,12,13,14,15], but when added in an α-helical orientation to the x-ray construct (pdb code: 1DB1), prior to assembly minimization, it was observed that R402 (H11) formed Coulombic interactions with either E425 and S398 or S427 and S398 (see methods; Fig. 1C, pink ribbon in yellow circle).…”

Section: Intramolecular Electrostatic Stabilization Of the C-terminalmentioning

confidence: 99%

“…Alternatively, mutation of R158, an Arg residue local to R154 that does not directly contact H12 residues (Fig. 1C) [11], to an A, E or F, only reduced 1,25D's genomic efficacy to ∼20% of WT (Fig. 2,Table 1).…”

Section: Intramolecular Electrostatic Stabilization Of the C-terminalmentioning

confidence: 99%

“…1B), have shown that agonists occupy the same relative steric space in the VDR LBD, termed the genomic pocket (G-pocket), and stabilize only the closed helix-12 conformation (VDR-c1, Fig. 1C) [11,12,13,14,15]. Analysis of these VDR structures and molecular models with complete AF2-domains, reveal that unlike any other hormonally regulated NR, H12 is held in the closed conformation (c1) by three salt-bridges: 1) K264---E420 2) R154---K413/ R154---L414/ R154---D232 and 3) R402---S427/ S398/ E425 (Fig.…”

Section: Introductionmentioning

confidence: 99%

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New insights into Vitamin D sterol-VDR proteolysis, allostery, structure–function from the perspective of a conformational ensemble model

Mizwicki

Bula

Bishop

et al. 2007

The Journal of Steroid Biochemistry and Molecular Biology

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Recently, we have developed a vitamin D sterol (VDS)-VDR conformational ensemble model. This model can be broken down into three individual, yet interlinked parts: a) the conformationally flexible VDS, b) the apo/holo-VDR helix-12 (H12) conformational ensemble, and c) the presence of two VDR ligand binding pockets (LBPs); one thermodynamically favored (the genomic pocket, Gpocket) and the other kinetically favored by VDSs (the alternative pocket, A-pocket). One focus of this study is to use directed VDR mutagenesis to 1) demonstrate H12 is stabilized in the transcriptionally active closed conformation (hVDR-c1) by three salt-bridges that span the length of H12 (cationic residues R154, K264 and R402), 2) to elucidate the VDR trypsin sites [R173 (hVDRc1), K413 (hVDR-c2) and R402 (hVDR-c3)] and 3) demonstrate the apo-VDR H12 equilibrium can be shifted. The other focus of this study is to apply the model to generate a mechanistic understanding to discrepancies observed in structure-function data obtained with a variety of 1α,25(OH) 2 -vitamin D 3 (1,25D) A-ring and side-chain analogs, and side-chain metabolites. We will demonstrate that these structure-function conundrums can be rationalized, for the most part by focusing on alterations in the VDS conformational flexibility and the elementary interaction between the VDS and the VDR A-and G-pockets, relative to the control, 1,25D.

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Section: Introductionmentioning

confidence: 81%

Section: Intramolecular Electrostatic Stabilization Of the C-terminalmentioning

confidence: 99%

Section: Intramolecular Electrostatic Stabilization Of the C-terminalmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

New insights into Vitamin D sterol-VDR proteolysis, allostery, structure–function from the perspective of a conformational ensemble model

Mizwicki

Bula

Bishop

et al. 2007

The Journal of Steroid Biochemistry and Molecular Biology

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“…Crucial to 1,25D-hVDR Transactivation-Based on the hVDR x-ray crystallographic results (5,(25)(26)(27) His-305 and His-397 form hydrogen bonds (H-bonds) with the 25-OH group of 1,25D (28,29) (Fig. 2).…”

Section: Vdw Contacts Made With Helix-3 and Helix-12 Residues Arementioning

confidence: 99%

On the Mechanism Underlying (23S)-25-Dehydro-1α(OH)-vitamin D3-26,23-lactone Antagonism of hVDRwt Gene Activation and Its Switch to a Superagonist

Mizwicki

Bula

Mahinthichaichan

et al. 2009

Journal of Biological Chemistry

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The steroid hormone 1␣,25(OH) 2 -vitamin D 3 (1,25D) 2 (see Fig. 1) and the nuclear vitamin D receptor (VDR) forms a complex that modulates the transcription of genes containing a VDR element. This process is termed a genomic response and involves 1,25D binding to the VDR, formation of a heterodimer with retinoid X receptor, and recruitment of nuclear co-activators (NCoAs) and the basal transcription machinery (1).The VDR is a member of the nuclear hormone superfamily of transcription factors, all of which share similar domain partitioning, ligand binding domain (LBD) tertiary fold and localization of their ligand binding pocket (LBP). The current inducedfit model describing nuclear receptor (NR) activation (i.e. the mouse-trap model) is founded on the comparison of apo-and holo-NR x-ray crystal structures. The mouse trap model posits that closure of the NR activation helix (i.e. helix-12) is induced by ligand binding to an opened-like helix-12 apo-NR conformer. The closed helix-12 conformation completes the activation function II domain (AF2), which serves as the high affinity binding site for recruitment of various NCoAs (1-4) (Fig. 2). Thus, the steric blockage of NR helix-12 closure is the basis for the design of traditional NR genomic antagonists (5-9).

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X‐Ray Crystallography in Drug Discovery

Livingston¹,

Buchanan²,

D’Amico³

et al. 2003

Burger's Medicinal Chemistry and Drug Discovery

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The focus of this chapter is the methods, recent advances, and the applications of X‐ray protein crystallography in the discovery of new drug targets and candidate drugs. It begins with a basic description of the various steps involved in solving a structure, including recent advances in technique and technology, and the major challenges that are faced in executing the process. The underlying theory, various crystallization methods, data collection equipment and techniques, and computational reduction of the data to give the final structure are all covered in this section. The accessible databases that contain large collections of structures are also described. The application to drug discovery is then briefly addressed with a discussion of co‐crystallization methods and issues, which is followed by a comprehensive table enumerating the published structures of the known drug targets and close homologs. Applications to discovering and validating protein targets of therapeutic relevance are then covered in a section on the very new field of structural genomics. Genome annotation by structural homology, elucidating pathways and the potential for the rational design of multitarget drugs, and advances in the field of protein structure modeling that are enabled by crystallographic databases are described and exemplified with very recent results from the field.

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The Crystal Structure of the Nuclear Receptor for Vitamin D Bound to Its Natural Ligand

Cited by 764 publications

References 32 publications

New insights into Vitamin D sterol-VDR proteolysis, allostery, structure–function from the perspective of a conformational ensemble model

New insights into Vitamin D sterol-VDR proteolysis, allostery, structure–function from the perspective of a conformational ensemble model

On the Mechanism Underlying (23S)-25-Dehydro-1α(OH)-vitamin D3-26,23-lactone Antagonism of hVDRwt Gene Activation and Its Switch to a Superagonist

X‐Ray Crystallography in Drug Discovery

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