The Structure of the KinA-Sda Complex Suggests an Allosteric Mechanism of Histidine Kinase Inhibition

Whitten, Andrew E.; Jacques, D.A.; Hammouda, Boualem; Hanley, Tracey; King, Glenn F.; Guss, J. Mitchell; Trewhella, Jill; Langley, David B.

doi:10.1016/j.jmb.2007.01.064

Cited by 80 publications

(112 citation statements)

References 39 publications

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“…That leaves two alternative models: (i) Sda induces a large conformational change that pivots the CA domain away from the DHp domain, or (ii) Sda induces a conformational change within the DHp domain that impairs interactions with the CA domain (similar to steric hindrance) or that repositions residues required for catalysis. Consistent with the model that Sda inhibits autophosphorylation by inducing a global conformational change, the KinA-Sda complex was observed to form a more compact structure compared with KinA alone, based on the low-angle X-ray scattering data (Whitten et al, 2007).…”

Section: Discussionsupporting

confidence: 78%

“…In addition, a proline residue that is part of a conserved sequence surrounding His-405, Pro-410, is important for Sda binding in vitro and inhibition by Sda and KipI in vivo. Although our data are consistent with the low-resolution model for the KinA-Sda complex (Whitten et al, 2007), they also raise the possibility that the binding site may include residues closer to His-405 than predicted by the model. In that case, Sda might inhibit both autophosphorylation and phosphotransfer from KinA~P to Spo0F by steric hindrance.…”

Section: Introductionsupporting

confidence: 84%

“…The large size of KipI and its predicted binding interface with KinA are consistent with the model that inhibition occurs by steric hindrance, although the overall structure of the complex is more compact than that of free KinA, suggesting that a global conformational change may also occur (Jacques et al, 2008). In contrast, the model of the KinA-Sda complex suggests that Sda may bind far enough away from the site of autophosphorylation so as not to sterically hinder interactions between the DHp and CA domains (Whitten et al, 2007). Like the KinA-KipI complex, the structure of the KinA-Sda complex is more compact than that of free KinA, consistent with Sda inducing a global conformational change in KinA.…”

Section: Introductionsupporting

confidence: 72%

“…Subsequent biophysical studies using small-angle X-ray scattering and neutron contrast variation provide strong evidence that Sda does not bind near the linker, but close to the other end of the DHp domain (Whitten et al, 2007). The structural model for the KinASda complex that provided the best fit to the data placed Sda far enough away from the site of autophosphorylation, His-405, and in an orientation such that it seemed unlikely that Sda would inhibit autophosphorylation by steric hindrance.…”

Section: Discussionmentioning

confidence: 99%

“…Spo0F interacts with the phosphorylated DHp domain and promotes the transfer of phosphate from the histidyl side-chain of KinA to a conserved aspartyl residue in Spo0F. Sda and KipI both bind the DHp domain of KinA (Rowland et al, 2004;Whitten et al, 2007;Jacques et al, 2008) and inhibit both autophosphorylation and the reverse reaction, the transfer of phosphate from KinA~P to ADP (Wang et al, 1997;Rowland et al, 2004). Even though Sda and KipI both bind KinA~P, as evidenced by their ability to inhibit the transfer of phosphate to ADP, neither protein has been observed to inhibit the transfer of phosphate from KinA~P to Spo0F (Wang et al, 1997;Rowland et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

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The histidine kinase inhibitor Sda binds near the site of autophosphorylation and may sterically hinder autophosphorylation and phosphotransfer to Spo0F

Cunningham

Burkholder²

2009

Molecular Microbiology

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SummaryHistidine kinases are widely used by bacteria, fungi and plants to sense and respond to changing environmental conditions. Signals in addition to those directly sensed by the kinase are often integrated by proteins that fine-tune the biological response by modulating the activity of the kinase or its targets. The Bacillus subtilis histidine kinase KinA promotes the initiation of sporulation when nutrients are limiting, but sporulation can be delayed by two inhibitors of KinA, Sda (when DNA replication is perturbed) or KipI (under unknown conditions). We have identified residues in the dimerization/histidinephosphotransfer (DHp) domain of KinA that are functionally important for inhibition by Sda and KipI and overlapping surface-exposed residues that lie close to or comprise the Sda binding site. Sda inhibits the intermolecular transfer of phosphate from the catalytic ATP-binding (CA) domain of KinA to the autophosphorylation site in the DHp domain when the domains are split into separate polypeptides, either by steric hindrance or by altering the conformation of the DHp domain. Sda also slows the rate of phosphotransfer from KinA~P to its target, Spo0F, consistent with our finding that a KinA residue important for Sda function overlaps with the predicted Spo0F binding site on KinA.

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Section: Discussionsupporting

confidence: 78%

Section: Introductionsupporting

confidence: 84%

Section: Introductionsupporting

confidence: 72%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The histidine kinase inhibitor Sda binds near the site of autophosphorylation and may sterically hinder autophosphorylation and phosphotransfer to Spo0F

Cunningham

Burkholder²

2009

Molecular Microbiology

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Neutron Scattering Techniques and Applications in Structural Biology

et al. 2013

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Neutron scattering is exquisitely sensitive to the position, concentration, and dynamics of hydrogen atoms in materials and is a powerful tool for the characterization of structure-function and interfacial relationships in biological systems. Modern neutron scattering facilities offer access to a sophisticated, nondestructive suite of instruments for biophysical characterization that provides spatial and dynamic information spanning from Ångstroms to microns and from picoseconds to microseconds, respectively. Applications in structural biology range from the atomic-resolution analysis of individual hydrogen atoms in enzymes through to meso- and macro-scale analysis of complex biological structures, membranes, and assemblies. The large difference in neutron scattering length between hydrogen and deuterium allows contrast variation experiments to be performed and enables H/D isotopic labeling to be used for selective and systematic analysis of the local structure, dynamics, and interactions of multi-component systems. This overview describes the available techniques and summarizes their practical application to the study of biomolecular systems.

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Small‐angle Scattering of Neutrons and X‐rays

Nadvi

Chow

Trewhella

2010

Encyclopedia of Life Sciences

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Small‐angle scattering of X‐rays and neutrons is used to study the structures of biological macromolecules in solution. Where the components of biomolecular complexes have different scattering densities, scattering data provide structural information on the individual components and their relative dispositions. One can therefore gain insights into protein–protein and protein– deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) interactions within functional complexes. Although scattering data are inherently low resolution and limited in information content due to the random orientations of the scattering molecules, recent applications that use data from complementary methods have facilitated the interpretation of scattering data in terms of detailed models. Advances in computational methods and user interfaces have enabled nonspecialists to use the technique to advance our understanding of biomolecular systems. The increasing availability of synchrotron facilities has also enabled advances in studies of time‐dependent changes in protein structure and the development of high‐throughput approaches. Key concepts: Small‐angle scattering provides information on the shapes of biological macromolecules in solution. Neutron contrast variation reveals the structures and disposition of the components within biomolecular complexes and assemblies. Proteins and polynucleotides naturally have different scattering densities for X‐rays and neutrons and can therefore be distinguished in a scattering experiment. Protein deuteration combined with systematic variation in solvent detueration can provide enhanced contrast variation capability for protein complexes. Small‐angle solution scattering data complements the higher resolution structural data from crystallography and NMR. Small‐angle scattering improves solution structure determination by providing information on long‐range distances that complements the predominantly short‐range distance information obtained by NMR. Solution scattering data complements high‐resolution crystallography by providing insights into conformational dynamics that are observed as a result of ligand binding or other changes in biological state. Synchrotron X‐ray sources enable time‐resolved solution scattering experiments to probe conformational dynamics in proteins and DNA or RNA. Structural characterization by small‐angle scattering requires highly pure, monodisperse identical particles in solution.

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The Structure of the KinA-Sda Complex Suggests an Allosteric Mechanism of Histidine Kinase Inhibition

Cited by 80 publications

References 39 publications

The histidine kinase inhibitor Sda binds near the site of autophosphorylation and may sterically hinder autophosphorylation and phosphotransfer to Spo0F

The histidine kinase inhibitor Sda binds near the site of autophosphorylation and may sterically hinder autophosphorylation and phosphotransfer to Spo0F

Neutron Scattering Techniques and Applications in Structural Biology

Small‐angle Scattering of Neutrons and X‐rays

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