Flexibility and Conformational Entropy in Protein-Protein Binding

Grünberg, Raik; Nilges, Michaël; Leckner, Johan

doi:10.1016/j.str.2006.01.014

Cited by 131 publications

(81 citation statements)

References 77 publications

(114 reference statements)

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“…It is interesting that additional connectivity in these regions softens the twist mode, so as to lower the energy of motion along it. If an analogous effect occurred in actually binding a ligand, it would be in accord with the increase in entropy calculated for other systems (23).…”

Section: Resultssupporting

confidence: 72%

Implications of the quaternary twist allosteric model for the physiology and pathology of nicotinic acetylcholine receptors

Taly

Corringer

Grütter

et al. 2006

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

108

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Nicotinic acetylcholine receptors (nAChR) are pentameric ligandgated ion channels composed of subunits that consist of an extracellular domain that carries the ligand-binding site and a distinct ion-pore domain. Signal transduction results from the allosteric coupling between the two domains: the distance from the binding site to the gate of the pore domain is 50 Å. Normal mode analysis with a C␣ Gaussian network of a new structural model of the neuronal ␣7 nAChR showed that the lowest mode involves a global quaternary twist motion that opens the ion pore. A molecular probe analysis, in which the network is modified at each individual amino acid residue, demonstrated that the major effect is to change the frequency, but not the form, of the twist mode. The largest effects were observed for the ligand-binding site and the Cys-loop. Most (24͞27) of spontaneous mutations known to cause congenital myasthenia and autosomal dominant nocturnal frontal lobe epilepsy are located either at the interface between subunits or, within a given subunit, at the interface between rigid blocks. These interfaces are modified significantly by the twist mode. The present analysis, thus, supports the quaternary twist model of the nAChR allosteric transition and provides a qualitative interpretation of the effect of the mutations responsible for several receptor pathologies.allosteric transition ͉ nicotinic receptor ͉ pathological mutations ͉ normal mode perturbation scanning N icotinic acetylcholine receptors (nAChRs) play a central role in intercellular communications in the brain and at the neuromuscular junction. They are involved in nicotine addiction as well as in cognitive processes such as attention, access to consciousness, learning, and memory, and their pathologies include autism, schizophrenia, Parkinson's disease, and Alzheimer's disease (references in ref. 1). Understanding the functional organization of the nAChR at the atomic level thus is of considerable interest in itself and is a source of insights for the development of new drug therapies.nAChRs are members of the Cys-loop superfamily of ligandgated ion channels. They are hetero-or homopentameric integral membrane proteins with a fivefold axis of pseudosymmetry perpendicular to the membrane. Each subunit can be subdivided into two principal domains: extracellular and transmembrane. The extracellular domain (ECD) carries the acetylcholine (ACh) binding site at the boundary between subunits, and the transmembrane ion-pore domain (IPD) delineates an axial cation-specific channel (2, 3). These topologically distinct domains are coupled allosterically to each other. Therefore, nAChRs possess the structural elements necessary to convert a chemical signal, typically a local increase of extracellular ACh concentration, into an electrical signal generated by the opening of the ion channel.Electrophysiological analysis of nAChRs has shown that rapid delivery of ACh promotes fast opening of the channel, and that a prolonged application of ACh leads to a slow decrease of the re...

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Section: Resultssupporting

confidence: 72%

Implications of the quaternary twist allosteric model for the physiology and pathology of nicotinic acetylcholine receptors

Taly

Corringer

Grütter

et al. 2006

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

108

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“…However, the flexibility of the linker as well as the cooperative stabilization of the UIM helix can overcome the entropic penalty. One has to keep in mind that flexibility has an important influence on the thermodynamics of binding and may both favor and disfavor association (56). In the light of our results, the differences between the binding of VHS-UIM to mono-Ub, Lys 48 (54) demonstrated that the linker length and composition modulated the affinity of RAP80-tUIM for Lys 63 -Ub 2 in a periodic fashion.…”

Section: Discussionmentioning

confidence: 64%

Evidence for Cooperative and Domain-specific Binding of the Signal Transducing Adaptor Molecule 2 (STAM2) to Lys63-linked Diubiquitin

Lange

Castañeda

Hoeller

et al. 2012

Journal of Biological Chemistry

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Background:The STAM2/Hrs complex is part of the ESCRT-0 (endosomal sorting complexes required for transport) machinery responsible for cargo sorting to the lysosome. Results: Binding of the VHS-UIM construct of STAM2 to Lys 63 -linked diubiquitin is cooperative with a specific structural organization. Conclusion: Spatial arrangement of the VHS-UIM/Lys63 -linked diubiquitin complex probably influences the sorting of Lys

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“…In protein-protein interactions, the enthalpy driving force is related to the change in the entire noncovalent energy upon binding, whereas entropy is affected by conformational changes and water displacement from the interface (85,86). Previous studies have shown that one-third of all interface residues are observed to undergo conformational changes (87,88).…”

Section: Discussionmentioning

confidence: 99%

Analysis of the Binding Forces Driving the Tight Interactions between β-Lactamase Inhibitory Protein-II (BLIP-II) and Class A β-Lactamases

Brown¹,

Chow²,

Sankaran

et al. 2011

Journal of Biological Chemistry

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␤-Lactamases hydrolyze ␤-lactam antibiotics to provide drug resistance to bacteria. ␤-Lactamase inhibitory protein-II (BLIP-II) is a potent proteinaceous inhibitor that exhibits low picomolar affinity for class A ␤-lactamases. This study examines the driving forces for binding between BLIP-II and ␤-lactamases using a combination of presteady state kinetics, isothermal titration calorimetry, and x-ray crystallography. The measured dissociation rate constants for BLIP-II and various ␤-lactamases ranged from 10 ؊4 to 10 ؊7 s ؊1 and are comparable with those found in some of the tightest known protein-protein interactions. The crystal structures of BLIP-II alone and in complex with Bacillus anthracis Bla1 ␤-lactamase revealed no significant side-chain movement in BLIP-II in the complex versus the monomer. The structural rigidity of BLIP-II minimizes the loss of the entropy upon complex formation and, as indicated by thermodynamics experiments, may be a key determinant of the observed potent inhibition of ␤-lactamases.Protein-protein interactions govern many cellular processes, and an understanding of the determinants of molecular recognition would facilitate the rationale design of interactions for therapeutic purposes. Detailed examination of kinetic constants and thermodynamic driving forces, however, has been performed for relatively few protein-protein interaction complexes. Although significant progress has been made in the understanding and prediction of association rate constants, the determinants of dissociation rates remain poorly understood (1-5). The ability to predict the kinetic constants would be a significant contribution to the understanding of interaction networks in the systems biology era (6). Several model systems have been developed to analyze the principles of protein-protein interactions, and one such model is the interaction between ␤-lactamase enzymes and a set of ␤-lactamase inhibitory proteins (BLIPs) 3 (7, 8). ␤-Lactamases act by hydrolyzing the four-membered ring of ␤-lactam antibiotics, e.g. penicillins and cephalosporins, rendering the drugs inactive (9, 10). There are four classes of ␤-lactamases (A-D) based on primary amino acid sequences (11,12). Class B ␤-lactamases are metalloenzymes that use a zinc-coordinated catalytic water to hydrolyze the ␤-lactam ring whereas classes A, C, and D are serine hydrolyases (13-15). Class A ␤-lactamases are widespread in both Gram-positive and Gramnegative bacteria and exhibit broad substrate hydrolysis profiles that include penicillins, cephalosporins, and for a few enzymes, carbapenems (12,14).The catalytic mechanism of serine ␤-lactamases is divided into two stages, acylation and deacylation (16). In class A enzymes, the catalytic Ser-70 residue nucleophilically attacks the carbonyl of the ␤-lactam and forms an acyl-intermediate (17,18). An essential Glu-166 residue activates a highly coordinated water for deacylation (18,19). Substitutions at Glu-166 result in an acylated, inactive enzyme (20 -22).Clinically available mechanism-based inhibitor...

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Flexibility and Conformational Entropy in Protein-Protein Binding

Cited by 131 publications

References 77 publications

Implications of the quaternary twist allosteric model for the physiology and pathology of nicotinic acetylcholine receptors

Implications of the quaternary twist allosteric model for the physiology and pathology of nicotinic acetylcholine receptors

Evidence for Cooperative and Domain-specific Binding of the Signal Transducing Adaptor Molecule 2 (STAM2) to Lys63-linked Diubiquitin

Analysis of the Binding Forces Driving the Tight Interactions between β-Lactamase Inhibitory Protein-II (BLIP-II) and Class A β-Lactamases

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