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The Sampling of Conformational Dynamics in Ambient-Temperature Crystal Structures of Arginine Kinase.

ABSTRACT: Arginine kinase provides a model for functional dynamics, studied through crystallography, enzymology, and nuclear magnetic resonance. Structures are now solved, at ambient temperature, for the transition state analog (TSA) complex. Analysis of quasi-rigid sub-domain displacements show that differences between the two TSA structures average about 5% of changes between substrate-free and TSA forms, and they are nearly co-linear. Small backbone hinge rotations map to sites that also flex on substrate binding. Anisotropic atomic displacement parameters (ADPs) are refined using rigid-body TLS constraints. Consistency between crystal forms shows that they reflect intrinsic molecular properties more than crystal lattice effects. In many regions, the favored directions of thermal/static displacement are appreciably correlated with movements on substrate binding. Correlation between ADPs and larger substrate-associated movements implies that the latter approximately follow paths of low-energy intrinsic motions.

SUBMITTER: Godsey MH

PROVIDER: S-EPMC5052116 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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The Sampling of Conformational Dynamics in Ambient-Temperature Crystal Structures of Arginine Kinase.

Godsey Michael H MH Davulcu Omar O Nix Jay C JC Skalicky Jack J JJ Brüschweiler Rafael P RP Chapman Michael S MS

Structure (London, England : 1993) 20160901 10

Arginine kinase provides a model for functional dynamics, studied through crystallography, enzymology, and nuclear magnetic resonance. Structures are now solved, at ambient temperature, for the transition state analog (TSA) complex. Analysis of quasi-rigid sub-domain displacements show that differences between the two TSA structures average about 5% of changes between substrate-free and TSA forms, and they are nearly co-linear. Small backbone hinge rotations map to sites that also flex on substr ...[more]

PMID: 27594681

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Project description:In order for protein kinases to exchange nucleotide they must open and close their catalytic cleft. These motions are associated with rotations of the N-lobe, predominantly around the 'hinge region'. We conducted an analysis of 28 crystal structures of the serine-threonine kinase, p21-activated kinase 4 (PAK4), including three newly determined structures in complex with staurosporine, FRAX486, and fasudil (HA-1077). We find an unusual motion between the N-lobe and C-lobe of PAK4 that manifests as a partial unwinding of helix αC. Principal component analysis of the crystal structures rationalizes these movements into three major states, and analysis of the kinase hydrophobic spines indicates concerted movements that create an accessible back pocket cavity. The conformational changes that we observe for PAK4 differ from previous descriptions of kinase motions, and although we observe these differences in crystal structures there is the possibility that the movements observed may suggest a diversity of kinase conformational changes associated with regulation.Author summaryProtein kinases are key signaling proteins, and are important drug targets, therefore understanding their regulation is important for both basic research and clinical points of view. In this study, we observe unusual conformational 'hinging' for protein kinases. Hinging, the opening and closing of the kinase sub-domains to allow nucleotide binding and release, is critical for proper kinase regulation and for targeted drug discovery. We determine new crystal structures of PAK4, an important Rho-effector kinase, and conduct analyses of these and previously determined structures. We find that PAK4 crystal structures can be classified into specific conformational groups, and that these groups are associated with previously unobserved hinging motions and an unusual conformation for the kinase hydrophobic core. Our findings therefore indicate that there may be a diversity of kinase hinging motions, and that these may indicate different mechanisms of regulation.

Dataset Information

The Sampling of Conformational Dynamics in Ambient-Temperature Crystal Structures of Arginine Kinase.

Publications

The Sampling of Conformational Dynamics in Ambient-Temperature Crystal Structures of Arginine Kinase.

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