Crystal structure and mutational analysis of the human CDK2 kinase complex with cell cycle-regulatory protein CksHs1

Y Bourne; M H Watson; M J Hickey; W Holmes; W Rocque; S I Reed; J A Tainer

doi:10.1016/s0092-8674(00)81065-x

Crystal structure and mutational analysis of the human CDK2 kinase complex with cell cycle-regulatory protein CksHs1

Cell. 1996 Mar 22;84(6):863-74. doi: 10.1016/s0092-8674(00)81065-x.

Authors

Y Bourne¹, M H Watson, M J Hickey, W Holmes, W Rocque, S I Reed, J A Tainer

Affiliation

¹ Department of Molecular Biology, Scripps Research Institute, La Jolla, California, 92037, USA.

PMID: 8601310
DOI: 10.1016/s0092-8674(00)81065-x

Abstract

The 2.6 Angstrom crystal structure for human cyclin-dependent kinase 2(CDK2) in complex with CksHs1, a human homolog of essential yeast cell cycle-regulatory proteins suc1 and Cks1, reveals that CksHs1 binds via all four beta strands to the kinase C-terminal lobe. This interface is biologically critical, based upon mutational analysis, but far from the CDK2 N-terminal lobe, cyclin, and regulatory phosphorylation sites. CDK2 binds the Cks single domain conformation and interacts with conserved hydrophobic residues plus His-60 and Glu-63 in their closed beta-hinge motif conformation. The beta hinge opening to form the Cks beta-interchanged dimer sterically precludes CDK2 binding, providing a possible mechanism regulating CDK2-Cks interactions. One face of the complex exposes the sequence-conserved phosphate-binding region on Cks and the ATP-binding site on CDK2, suggesting that CKs may target CDK2 to other phosphoproteins during the cell cycle.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Base Sequence
CDC2-CDC28 Kinases*
Carrier Proteins / chemistry*
Carrier Proteins / genetics
Carrier Proteins / metabolism
Cell Cycle / physiology
Cell Cycle Proteins*
Conserved Sequence
Crystallography
Cyclin-Dependent Kinase 2
Cyclin-Dependent Kinases / chemistry*
Cyclin-Dependent Kinases / genetics
Cyclin-Dependent Kinases / metabolism
DNA Mutational Analysis
Humans
Image Processing, Computer-Assisted
Molecular Sequence Data
Protein Binding / physiology
Protein Conformation
Protein Kinases*
Protein Serine-Threonine Kinases / chemistry*
Protein Serine-Threonine Kinases / genetics
Protein Serine-Threonine Kinases / metabolism
Saccharomyces cerevisiae / genetics
Sensitivity and Specificity
Sequence Homology, Amino Acid

Substances

CKS1B protein, human
Carrier Proteins
Cell Cycle Proteins
Protein Kinases
Protein Serine-Threonine Kinases
CDC2-CDC28 Kinases
CDK2 protein, human
CKS2 protein, human
Cyclin-Dependent Kinase 2
Cyclin-Dependent Kinases