Protein side-chain conformation: a systematic variation of χ<sub>1</sub>mean values with resolution – a consequence of multiple rotameric states?

MacArthur, Malcolm W.; Thornton, Janet M.

doi:10.1107/s0907444999002231

Cited by 38 publications

(46 citation statements)

References 22 publications

(15 reference statements)

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“…Almost half of the phosphates in the duplex show multiple conformations. A similar situation has been found in high resolution structures of proteins, which show multiple side chain conformations (37). Such variability should be interpreted as static disorder at the temperature (120 K) of the experiment.…”

Section: Discussionsupporting

confidence: 74%

Solvent Organization in an Oligonucleotide Crystal

Soler-López¹,

Malinina²,

Subirana³

2000

Journal of Biological Chemistry

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We describe the crystal structure of d(GCGAATTCG) determined by x-ray diffraction at atomic resolution level (0.89 Å). The duplex structure is practically identical to that described at 2.05 Å resolution (Van Meervelt, L., Vlieghe, D., Dautant, A., Gallois, B., Pré cigoux, G., and Kennard, O. (1995) Nature 374, 742-744), however about half of the phosphate groups show multiple conformations. The crystal has three regions with different solvent structure. One of them contains several ordered Mg ؉2 ions and can be considered as an ionic crystal. A second region is formed by a network of ordered water molecules with a polygonal organization that binds three duplexes. The third region is formed by channels of solvent in which very few ordered solvent molecules are visible. The less ordered phosphates are found facing this channel. The latter region provides a view of DNA with highly movable charges, both negative phosphates and counterions, without a precise location.Two periods could be distinguished in the x-ray diffraction studies of DNA: the era of fiber diffraction of polymeric DNA/ polynucleotides and the time of single crystal x-ray structures of short fragments. The data available from fiber diffraction were limited and allowed no detailed analysis. The goal of DNA crystallography is, therefore, the study of detailed DNA structures. However, crystallographic data are also limited in some important aspects of DNA structure. For example, it is well known (1) that the solvent environment plays an important role in the conformational behavior and interactions of DNA. To study this feature in detail, it is necessary to work with x-ray data at atomic resolution level. Until recently, such data were available only for Z-DNA fragments. This situation is now changing. Synchrotron radiation of increasing power, together with better detectors and cryotechniques, make possible a third period of DNA crystallography: the epoch of high resolution DNA structures.We recently presented (2) a preliminary account of the structure of the B-DNA fragment (GCGAATTCG) solved at atomic resolution (0.89 Å). This structure had already been solved at 2.05-Å resolution (3, 4). In our previous analysis we described the water spine in the minor groove and compared it with related structures. Here we present a detailed analysis of the same oligonucleotide, which has multiple conformations in several parts of the phosphodiester backbone. We also describe the organization of the solvent, which in some regions shows well resolved water molecules, whereas in other regions it remains disordered, despite the fact that our crystals have been studied at 120 K. Thus, a frozen sample at atomic resolution, instead of showing a highly ordered duplex, demonstrates multiple conformations and regions of disordered solvent. MATERIALS AND METHODSCrystallization-The d(GCGAATTCG) nonamer was crystallized, using a batch method, in sitting drops containing 0.5 mM DNA duplex, 1 mM acridine-(Arg 4 ) drug-peptide aduct, 20 mM sodium cacodylate buffer, pH 7, 100 mM...

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Section: Discussionsupporting

confidence: 74%

Solvent Organization in an Oligonucleotide Crystal

Soler-López¹,

Malinina²,

Subirana³

2000

Journal of Biological Chemistry

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“…Traffic 2000: 1: 270-281 that observed at low resolution, a feature noted in other high resolution structures (13). Third, three methionine residues (Met 33, 66 and 82) also adopt two discrete side-chain conformations ( Figure 1B).…”

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confidence: 66%

A New Functional Domain of Guanine Nucleotide Dissociation Inhibitor (α‐GDI) Involved in Rab Recycling

Luan

Heine

Zeng

et al. 2000

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Guanine nucleotide dissociation inhibitor (GDI) is a 55-kDa protein that functions in vesicular membrane transport to recycle Rab GTPases. We have now determined the crystal structure of bovine a-GDI at ultra-high resolution (1.04 A , ). Refinement at this resolution highlighted a region with high mobility of its main-chain residues. This corresponded to a surface loop in the primarily a-helical domain II at the base of a-GDI containing the previously uncharacterized sequence-conserved region (SCR) 3A. Site-directed mutagenesis showed that this mobile loop plays a crucial role in binding of GDI to membranes and extraction of membrane-bound Rab. This domain, referred to as the mobile effector loop, in combination with Rab-binding residues found in the multi-sheet domain I at the apex of a-GDI may provide flexibility for recycling of diverse Rab GTPases. We propose that conserved residues in domains I and II synergize to form the functional face of GDI, and that domain II mediates a critical step in Rab recycling during vesicle fusion.

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“…A higher number of multiple occupancies is expected with improvement in resolution. 14 Overall, when the model is compared to the 1.24 A resolution synPDZ2 structure, it shows an r.m.s. < difference for the main-chain atoms of 0.745 A for all residues, but the value is only 0.364 A when the N-terminal five residues and C-terminal two residues are excluded.…”

Section: Multiple Main Chain and Side-chain Conformationsmentioning

confidence: 99%

“…There are currently at least ten putative binding partners reported for syntenin, including IL-5 receptor a subunit (IL5Ra) [5], neuroglian [7], proTGF-a [3], glutamate receptors [8], neurofascin [7], syndecan-4 [1], ephrin B [9,10], ephrin A7 [9], PTP-m [11], neurexin I [12], and merlin [13]. All the binding partners of syntenin are receptors except for merlin, a cytosolic tumor repressor that is a product of the causal gene for type II neurofibromatosis (NF) [14]. Merlin belongs to the protein 4.1 superfamily, which also includes ezrin, moesin, and radixin, and like its homologs, it binds actin [15].…”

Section: Introductionmentioning

confidence: 99%

“…Subsequently, syntenin was also found to play a role in protein trafficking [2, 3] [13]. All the binding partners of syntenin are receptors except for merlin, a cytosolic tumor repressor that is a product of the causal gene for type II neurofibromatosis (NF) [14]. Merlin belongs to the protein 4.1 superfamily, which also includes ezrin, moesin, and radixin, and like its homologs, it binds actin [15].…”

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confidence: 99%

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Structure-Function Relationships in Merlin, the Product of the NF2 Causal Gene

Derewenda¹

2004

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the lime for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of Information, Including suggestions for reducing this burden to Washington Headquarters Services, Directorate for Information Operations and Reports, 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302 and to PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES)University of Virginia Charlottesville, VA 22904 E-Mail: Zsd4n@virginia. edu SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES)U 12b. DISTRIBUTION CODENeurofibromatosis type 2 (NF2) is a debilitating, inherited disorder characterized by tumors of the brain and central nervous system. It is caused by the lack of a functional product of the NF2 gene, known as merlin. Merlin serves as a linker protein between the cell membrane and the cytoskeleton. During the tenure of this grant, we used X-ray crystallography to determine the structure of the N-terminal FERM domain of merlin and we analyzed its functional implications. We also investigated structure-funtion relationships in syntenin, a scaffolding protein that binds to merlin. The structure of the PDZ tandem of syntenin was determined at 1.9 Ä resolution, and we also determined the structure of the 2 nd PDZ domain of syntenin to 0.73 Ä, making it one of the highest resolution protein structures determined thus far. Furthermore, the structures of numerous complexes of syntenin with peptide ligands were determined to gain a better understanding of peptide recognition by PDZ domains. This lead to the formulation of the "combinatorial" model of peptide recognition, which helps explain non-canonical PDZ domain specificities. Biophysical and biochemical techniques were used to characterize the interaction of the PDZ domains with peptides derived from syntenin binding partners including merlin, syndecan, and the interleukin 5 receptor a-subunit. SUBJECT TERMSNF2, merlin, crystallography, syntenin, protein-protein interactions Syndecan, interleukin 5 receptor CC, PDZ domain. Cover. SECURITY CLASSIFICATION OF REPORT UnclassifiedSF 298.Introduction. Body 5 Key Research Accomplishments 20Reportable Outcomes 21 Conclusions 24References 29Appendices 33 IntroductionNeurofibromatosis type 2 (NF2), characterized by tumors of the brain and central nervous system, is a debilitating, inherited disorder affecting 1 in 40,000 people (Evans et al., 2000). Genetic studies revealed that the disorder is caused by mutations in the NF2 gene which codes for a protein known as merlin or schwannomin (Lutchman and Rouleau, 1996). Merlin is a member of the ERM (Ezrin, Radixin, and Moesin) family of proteins, but it is unique in that it acts as a tumor suppressor . Merlin exists in two different splice forms with different C-termini, has no catalytic ac...

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Protein side-chain conformation: a systematic variation of χ₁mean values with resolution – a consequence of multiple rotameric states?

Cited by 38 publications

References 22 publications

Solvent Organization in an Oligonucleotide Crystal

Solvent Organization in an Oligonucleotide Crystal

A New Functional Domain of Guanine Nucleotide Dissociation Inhibitor (α‐GDI) Involved in Rab Recycling

Structure-Function Relationships in Merlin, the Product of the NF2 Causal Gene

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Protein side-chain conformation: a systematic variation of χ1mean values with resolution – a consequence of multiple rotameric states?

Cited by 38 publications

References 22 publications

Solvent Organization in an Oligonucleotide Crystal

Solvent Organization in an Oligonucleotide Crystal

A New Functional Domain of Guanine Nucleotide Dissociation Inhibitor (α‐GDI) Involved in Rab Recycling

Structure-Function Relationships in Merlin, the Product of the NF2 Causal Gene

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Product

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Protein side-chain conformation: a systematic variation of χ₁mean values with resolution – a consequence of multiple rotameric states?