On the multiple simultaneous superposition of molecular structures by rigid body transformations

Diamond, Robert M.

doi:10.1002/pro.5560011006

Cited by 114 publications

(109 citation statements)

References 17 publications

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“…CLUSTERPOSE (28) was used to calculate the mean rms deviation (rmsd) of these NMR ensembles from the mean structure as a function of ensemble size.…”

Section: Methodsmentioning

confidence: 99%

Structural insights into the interaction and activation of histone deacetylase 3 by nuclear receptor corepressors

Codina

Love²,

Li³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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SMRT (silencing mediator of retinoid acid and thyroid hormone receptor) and NCoR (nuclear receptor corepressor) are transcriptional corepressors that play an essential role in the regulation of development and metabolism. This role is achieved, in part, through the recruitment of a key histone deacetylase (HDAC3), which is itself indispensable for cell viability. The assembly of HDAC3 with the deacetylase activation domain (DAD) of SMRT and NCoR is required for activation of the otherwise inert deacetylase. The DAD comprises an N-terminal DAD-specific motif and a Cterminal SANT (SWI3͞ADA2͞NCoR͞TFIIIB)-like domain. We report here the solution structure of the DAD from SMRT, which reveals a four-helical structure. The DAD differs from the SANT (and MYB) domains in that (i) it has an additional N-terminal helix and (ii) there is a notable hydrophobic groove on the surface of the domain. Structure-guided mutagenesis, combined with interaction assays, showed that residues in the vicinity of the hydrophobic groove are required for interaction with (and hence activation of) HDAC3. Importantly, one surface-exposed lysine is required for activation of HDAC3, but not for interaction. This lysine may play a uniquely important role in the mechanism of activating HDAC3.NMR structure ͉ repression ͉ transcription

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“…CLUSTERPOSE (28) was used to calculate the mean rms deviation (rmsd) of these NMR ensembles from the mean structure as a function of ensemble size.…”

Section: Methodsmentioning

confidence: 99%

Structural insights into the interaction and activation of histone deacetylase 3 by nuclear receptor corepressors

Codina

Love²,

Li³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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“…Based on this information, we identified hinge residues. The CCP4 supported program POLYPOSE (19) was used to obtain the rotation matrix and rotation values required for superimposing secondary structural elements between the open and closed conformational states.…”

Section: Methodsmentioning

confidence: 99%

Substrate-induced Conformational Changes in Human UMP/CMP Kinase

Segura-Peña

Sekulić

Ort

et al. 2004

Journal of Biological Chemistry

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Human UMP/CMP kinase plays a crucial role in supplying precursors for nucleic acid synthesis by catalyzing the conversion of UMP, CMP, and dCMP into their diphosphate form. In addition, this kinase is an essential component of the activation cascade of medicinally relevant nucleoside analog prodrugs such as AraC, gemcitabine, and ddC. During the catalytic cycle the enzyme undergoes large conformational changes from open in the absence of substrates to closed in the presence of both phosphoryl donor and phosphoryl acceptor. Here we report the crystal structure of the substrate-free, open form of human UMP/CMP kinase. Comparison of the open structure with the closed state previously reported for the similar Dictyostelium discoideum UMP/CMP kinase reveals the conformational changes that occur upon substrate binding. We observe a classic example of induced fit where substrate-induced conformational changes in hinge residues result in rigid body movements of functional domains to form the catalytically competent state. In addition, a homology model of the human enzyme in the closed state based on the structure of D. discoideum UMP/CMP kinase aids to rationalize the substrate specificity of the human enzyme.UMP/CMP kinase plays a critical role in the pathway that supplies nucleotide precursors for DNA and RNA synthesis. The physiological substrates UMP, CMP, and dCMP are reversibly converted by UMP/CMP kinase into their diphosphate form according to the following reaction scheme.Subsequent phosphorylation by nucleoside diphosphate kinase results in the triphosphorylated form of these nucleotides, which are the substrates for DNA and RNA polymerases. Additionally, UMP/CMP kinase participates in the activation of clinically relevant nucleoside analog prodrugs that are used in cancer and viral chemotherapy. Therefore, understanding the determinants of substrate specificity, the precise roles played by its catalytic residues, and the conformational changes that take place during the catalytic cycle is of paramount importance for the development of more effective anti-cancer and anti-viral agents.Despite the physiological and medicinal importance of this enzyme, the human form was cloned only in 1999 (1). This work was followed by biochemical characterization of the enzyme, which revealed its ability to phosphorylate synthetic nucleosides (2-4). Important examples are the monophosphate form of the cytidine analogs 1-␤-D-arabinofuranosylcytosine (AraC) 1 and 2Ј,2Ј-difluorodeoxycytidine (gemcitabine), a mainstay of leukemia and lymphoma therapy. The first step in the conversion of these cytidine analogs to their pharmacologically active triphosphorylated form is catalyzed by deoxycytidine kinase. We have recently published the structure of human deoxycytidine kinase in complex with AraC, gemcitabine, and its physiological substrate deoxycytidine (5). The second step of AraC and gemcitabine activation, from the monophosphate to the diphosphate form, is catalyzed by UMP/CMP kinase. The third phosphate group is added by the non...

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“…It is important to note that . The superimposition using 132 C␣ atoms of CaM (residues 6 -72 and 83-147) was calculated using the CCP4 module Polypose (63). B, the ␣IIspec calmodulin-binding domain is tilted upward toward the second methionine cleft when compared with other CaM ligands.…”

Section: Cam-␣iispec Binding Is Mediated Entirely By Hydrophobicmentioning

confidence: 99%

“…This view is rotated ϳ90 o clockwise around the vertical axis relative to B (produced in Molscript (60) and rendered in Raster 3D (61)). The peptide ligand positions are generated upon superimposing C ␣ atoms of the N-and C-lobes of CaM using the CCP4 module Polypose (63). D, B factor (average main chain) versus residue plots for CaM-␣IIspec complex reveals flexible regions in CaM.…”

Section: Cam-␣iispec Binding Is Mediated Entirely By Hydrophobicmentioning

confidence: 99%

Structure of the Calmodulin αII-Spectrin Complex Provides Insight into the Regulation of Cell Plasticity

Simonović

Zhang

Cianci

et al. 2006

Journal of Biological Chemistry

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␣II-spectrin is a major cortical cytoskeletal protein contributing to membrane organization and integrity. The Ca 2؉ -activated binding of calmodulin to an unstructured insert in the 11th repeat unit of ␣II-spectrin enhances the susceptibility of spectrin to calpain cleavage but abolishes its sensitivity to several caspases and to at least one bacterially derived pathologic protease. Other regulatory inputs including phosphorylation by c-Src also modulate the proteolytic susceptibility of ␣II-spectrin. These pathways, acting through spectrin, appear to control membrane plasticity and integrity in several cell types. To provide a structural basis for understanding these crucial biological events, we have solved the crystal structure of a complex between bovine calmodulin and the calmodulinbinding domain of human ␣II-spectrin (Protein Data Bank ID code 2FOT). The structure revealed that the entire calmodulin-spectrin-binding interface is hydrophobic in nature. The spectrin domain is also unique in folding into an amphiphilic helix once positioned within the calmodulin-binding groove. The structure of this complex provides insight into the mechanisms by which calmodulin, calpain, caspase, and tyrosine phosphorylation act on spectrin to regulate essential cellular processes.Spectrin ␣␤ heterodimers are organized into filamentous structures composed of two related subunits. The ␣ subunit contains 21 triple-helical homologous repeats that are further organized into five protease-sensitive domains (1). The 11th repeat is the longest and contains a unique insert that is implicated to play a critical role in spectrin integrity. The spectrinbased cytoskeleton represents a scaffold attached to both the plasma membrane and the intracellular organelles by interactions involving both integral and peripheral membrane proteins as well as by direct lipid interactions (2-4). Spectrin integrity is critical for establishing organized membrane subdomains and their maintenance, supporting integral membrane protein durability (5, 6). Deletions in spectrin or dominant negative blockers of spectrin disrupt membrane-protein distributions and may lead to the total loss of critical signaling or transport proteins from the cell surface (7-10). Controlled spectrin proteolysis has been detected during both apoptotic and necrotic cell death processes (11-13), upon cell shape change (14), during cell differentiation (15-17), during lens development (18), and coincident with synaptic remodeling and dendrite outgrowth (19,20). It has been observed that during the early stages of apoptosis, a characteristic 150-kDa fragment of ␣II-spectrin is generated by caspases regardless of the cell type and the apoptosis stimulus (21). In neurons, calpain-catalyzed proteolysis has been linked with N-methyl-D-aspartate receptor activation and is thought to be crucial for synaptic and neuronal plasticity. Finally, the Pet toxin, a serine proteinase from enteropathogenic bacteria, catalyzes spectrin fragmentation and the consequent collapse of the cell membrane ...

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On the multiple simultaneous superposition of molecular structures by rigid body transformations

Cited by 114 publications

References 17 publications

Structural insights into the interaction and activation of histone deacetylase 3 by nuclear receptor corepressors

Structural insights into the interaction and activation of histone deacetylase 3 by nuclear receptor corepressors

Substrate-induced Conformational Changes in Human UMP/CMP Kinase

Structure of the Calmodulin αII-Spectrin Complex Provides Insight into the Regulation of Cell Plasticity

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