Mechanisms of domain closure in proteins.

Certain enzymes respond to the binding of substrates and coenzymes by the closure of an active site that lies in a cleft between two domains. We have examined the mechanism of the domain closure in citrate synthase, for which atomic co-ordinates are available for "open" and "closed" forms. We show that the mechanism of domain closure involves small shifts and rotations of packed helices within the two domains and at their interface. Large motions of distant segments of the structure are the cumulative effect of the small relative shifts in intervening pairs of packed segments. These shifts are accommodated not by changes in packing but rather by small conformational changes in side-chains. We call this the helix interface shear mechanism of domain closure. The relative movements of packed helices follow the principles suggested by our recent study of insulin. This mechanism of domain closure is quite different from the hinge mechanisms that allow the rigid body movements of domains in immunoglobulins. The large interface between the domains of citrate synthase precludes a simple hinge mechanism for its conformational change. The helix interface shear mechanism of conformational change occurs in other enzymes that contain extensive domain-domain interfaces.

[1]  J. Baldwin,et al.  The structure of human carbonmonoxy haemoglobin at 2.7 A resolution. , 1980, Journal of molecular biology.

[2]  T. Steitz,et al.  Structure of a complex between yeast hexokinase A and glucose. II. Detailed comparisons of conformation and active site configuration with the native hexokinase B monomer and dimer. , 1980, Journal of molecular biology.

[3]  T. A. Jones,et al.  Structure of a triclinic ternary complex of horse liver alcohol dehydrogenase at 2.9 A resolution. , 1981, Journal of molecular biology.

[4]  T. Steitz,et al.  Space-filling models of kinase clefts and conformation changes. , 1979, Science.

[5]  C. Chothia,et al.  Helix to helix packing in proteins. , 1981, Journal of molecular biology.

[6]  R. Huber,et al.  Functional significance of flexibility in proteins , 1982, Biopolymers.

[7]  H. Eklund,et al.  Crystal structure determinations of coenzyme analogue and substrate complexes of liver alcohol dehydrogenase: binding of 1,4,5,6-tetrahydronicotinamide adenine dinucleotide and trans-4-(N,N-dimethylamino)cinnamaldehyde to the enzyme. , 1982, Biochemistry.

[8]  C Chothia,et al.  Haemoglobin: the structural changes related to ligand binding and its allosteric mechanism. , 1979, Journal of molecular biology.

[9]  G J Williams,et al.  The Protein Data Bank: a computer-based archival file for macromolecular structures. , 1977, Journal of molecular biology.

[10]  J. Janin,et al.  Structural domains in proteins and their role in the dynamics of protein function. , 1983, Progress in biophysics and molecular biology.

[11]  F. Crick,et al.  The packing of α‐helices: simple coiled‐coils , 1953 .

[12]  G. Fermi,et al.  Three-dimensional fourier synthesis of human deoxyhaemoglobin at 2-5 A resolution: refinement of the atomic model. , 1975, Journal of molecular biology.

[13]  T. Steitz,et al.  A refined model of the sugar binding site of yeast hexokinase B. , 1978, Journal of molecular biology.

[14]  T. Steitz,et al.  Structural dynamics of yeast hexokinase during catalysis. , 1981, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[15]  H. Eklund,et al.  Three-dimensional structure of horse liver alcohol dehydrogenase at 2-4 A resolution. , 1976, Journal of molecular biology.

[16]  Cyrus Chothia,et al.  Transmission of conformational change in insulin , 1983, Nature.

[17]  R. Huber,et al.  Crystallographic refinement and atomic models of two different forms of citrate synthase at 2.7 and 1.7 A resolution. , 1984, Journal of molecular biology.

[18]  W. Kabsch.  A solution for the best rotation to relate two sets of vectors , 1976 .