Ligand Binding Induces Conformational Changes in Human Cellular Retinol-binding Protein 1 (CRBP1) Revealed by Atomic Resolution Crystal Structures

Silvaroli, J.A.; Arne, J.M.; Chełstowska, Sylwia; Kiser, Philip D.; Banerjee, Surajit; Golczak, Marcin

doi:10.1074/jbc.m116.714535

Cited by 46 publications

(61 citation statements)

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“…This progress has been driven by identification of novel proteins and the generation of numerous mouse models deficient in genes involved in vitamin A metabolism. In parallel with these efforts, structural biology provided valuable knowledge regarding molecular organization and a mode of action for retinoid-binding proteins [79], RPE65 [91,92], and LRAT [80]. Despite this indisputable progress, each new discovery raises additional questions reminding us how much more we need to learn about retinoid metabolism throughout the body.…”

Section: Discussionmentioning

confidence: 99%

“…Because the factors that contribute to the transport of vitamin A across the cytoplasm are not fully understood this process is illustrated by dashed arrows. Structures of RBP and retinol binding protein (here cellular retinol-binding protein 1, CRBP1) correspond to PDB accession numbers 1RBP [78] and 5H8T [79], respectively. STRA6 refers to the cryo-electron microscopy structure of zebrafish protein in complex with calmodulin (EM Data Bank #8315) [75].…”

Section: Figurementioning

confidence: 99%

“…The retinoid cycle is completed by transport of 11- cis -retinal back to the photoreceptors, where it conjugates with opsin and thus regenerates visual pigment. Structures of cellular retinol-binding protein 1 (CRBP1), retinoid isomerase (RPE65) and cellular retinaldehyde-binding protein (CRALBP) correspond to PDB accession numbers 5H8T [79], 3KVC [96], and 4CIZ [97], respectively. Generic model of 11- cis -retinol dehydrogenases (11- cis -RDHs) was built based on the structure of dehydrogenase from Drosophila melanogaster PDB accession number 5ILG.…”

Section: Figurementioning

confidence: 99%

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Molecular Basis for Vitamin A Uptake and Storage in Vertebrates

et al. 2016

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The ability to store and distribute vitamin A inside the body is the main evolutionary adaptation that allows vertebrates to maintain retinoid functions during nutritional deficiencies and to acquire new metabolic pathways enabling light-independent production of 11-cis retinoids. These processes greatly depend on enzymes that esterify vitamin A as well as associated retinoid binding proteins. Although the significance of retinyl esters for vitamin A homeostasis is well established, until recently, the molecular basis for the retinol esterification enzymatic activity was unknown. In this review, we will look at retinoid absorption through the prism of current biochemical and structural studies on vitamin A esterifying enzymes. We describe molecular adaptations that enable retinoid storage and delineate mechanisms in which mutations found in selective proteins might influence vitamin A homeostasis in affected patients.

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Section: Discussionmentioning

confidence: 99%

Section: Figurementioning

confidence: 99%

Section: Figurementioning

confidence: 99%

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Molecular Basis for Vitamin A Uptake and Storage in Vertebrates

et al. 2016

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“…S1) was formed from the crystallographic structure (PDB code: 5HBS)[38] by rotating it to the orientation of RTL is approximately along the z-axis, putting the complex in the center of a water box of 80 Å ×80 Å ×100 Å , and neutralizing the system and salinizing it to 150 mM with 61 Na + and 55 Cl − ions. During the 50 ns equilibrium MD run, the system settles down (after 4 ns) to fluctuate slightly around the dimensions of 78 Å × 78 Å ×97 Å .…”

Section: Methodsmentioning

confidence: 99%

“…These PMF-based approaches, delicate equilibrium or brute force nonequilibrium, have proven to be effective in cases where a small molecule (or protein) adheres onto the surface of a protein or resides in an open binding site and, therefore, can be removed from the protein along an unhindered path. [12, 15, 16, 28–37] However, are they applicable to the cases where a ligand is completely buried in a deep binding site such as the complex of retinol (RTL) bound inside the human cellular retinol-binding protein 1 (CRBP1)[38] illustrated in Fig. 2?…”

Section: Introductionmentioning

confidence: 99%

Computing the binding affinity of a ligand buried deep inside a protein with the hybrid steered molecular dynamics

Villarreal

Rodríguez

et al. 2017

Biochemical and Biophysical Research Communications

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Computing the ligand-protein binding affinity (or the Gibbs free energy) with chemical accuracy has long been a challenge for which many methods/approaches have been developed and refined with various successful applications. False positives and, even more harmful, false negatives have been and still are a common occurrence in practical applications. Inevitable in all approaches are the errors in the force field parameters we obtain from quantum mechanical computation and/or empirical fittings for the intra- and inter-molecular interactions. These errors propagate to the final results of the computed binding affinities even if we were able to perfectly implement the statistical mechanics of all the processes relevant to a given problem. And they are actually amplified to various degrees even in the mature, sophisticated computational approaches. In particular, the free energy perturbation (alchemical) approaches amplify the errors in the force field parameters because they rely on extracting the small differences between similarly large numbers. In this paper, we develop a hybrid steered molecular dynamics (hSMD) approach to the difficult binding problems of a ligand buried deep inside a protein. Sampling the transition along a physical (not alchemical) dissociation path of opening up the binding cavity---pulling out the ligand---closing back the cavity, we can avoid the problem of error amplifications by not relying on small differences between similar numbers. We tested this new form of hSMD on retinol inside cellular retinol-binding protein 1 and three cases of a ligand (a benzylacetate, a 2-nitrothiophene, and a benzene) inside a T4 lysozyme L99A/M102Q(H) double mutant. In all cases, we obtained binding free energies in close agreement with the experimentally measured values. This indicates that the force field parameters we employed are accurate and that hSMD (a brute force, unsophisticated approach) is free from the problem of error amplification suffered by many sophisticated approaches in the literature.

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Porins and Amyloids are Coded by Similar Sequence Motifs

2018

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The relationship between amino acid sequences of the β‐hairpin structures and amyloidogenic β‐arcade‐forming motifs are of special interest because, similar to amyloid fibrils, most of the β‐hairpin repeat (BHR) structures have the so‐called cross‐β arrangement. Moreover, β‐hairpin is considered as a probable intermediate structure in amyloidogenesis. In this work, a bioinformatics sequence analysis of the known BHR structures is performed in search of amylodogenic motifs able to form β‐arcade fibrils. The analysis shows that the occurrence of the predicted β‐arcade motifs in the BHR regions is very different depending on the BHR structural fold, cellular localization, and phylogeny. One of the most striking observations is the high level of sequence similarity between the BHRs of membranous porins and β‐arcade motifs. This sequence similarity provides additional evidence that the structure of the membranous porins and annular amyloid oligomers may bear a resemblance. Moreover, these results explain how some amyloidogenic sequence can fold in either the ring‐like shape oligomers or elongated amyloid fibrils. It has been also found that potentially lethal amyloidogenic β‐arcade motifs are absent in the elongated BHR structures of intracellular eukaryotic proteins. It allows to hypothesize that, in this case, the selective evolutionary pressure acts against aggregation.

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Ligand Binding Induces Conformational Changes in Human Cellular Retinol-binding Protein 1 (CRBP1) Revealed by Atomic Resolution Crystal Structures

Cited by 46 publications

References 61 publications

Molecular Basis for Vitamin A Uptake and Storage in Vertebrates

Molecular Basis for Vitamin A Uptake and Storage in Vertebrates

Computing the binding affinity of a ligand buried deep inside a protein with the hybrid steered molecular dynamics

Porins and Amyloids are Coded by Similar Sequence Motifs

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