Substrate-induced Conformational Changes in Human UMP/CMP Kinase
Human UMP/CMP kinase plays a crucial role in supplying precursors for nucleic acid synthesis by catalyzing the conversion of UMP, CMP, and dCMP into their diphosphate form. In addition, this kinase is an essential component of the activation cascade of medicinally relevant nucleoside analog prodrugs...
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| Veröffentlicht in: | The Journal of biological chemistry 2004-08, Vol.279 (32), p.33882-33889 |
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| container_issue | 32 |
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| container_title | The Journal of biological chemistry |
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| creator | Segura-Peña, Dario Sekulic, Nikolina Ort, Stephan Konrad, Manfred Lavie, Arnon |
| description | Human UMP/CMP kinase plays a crucial role in supplying precursors for nucleic acid synthesis by catalyzing the conversion of UMP, CMP, and dCMP into their diphosphate form. In addition, this kinase is an essential component of the activation cascade of medicinally relevant nucleoside analog prodrugs such as AraC, gemcitabine, and ddC. During the catalytic cycle the enzyme undergoes large conformational changes from open in the absence of substrates to closed in the presence of both phosphoryl donor and phosphoryl acceptor. Here we report the crystal structure of the substrate-free, open form of human UMP/CMP kinase. Comparison of the open structure with the closed state previously reported for the similar Dictyostelium discoideum UMP/CMP kinase reveals the conformational changes that occur upon substrate binding. We observe a classic example of induced fit where substrate-induced conformational changes in hinge residues result in rigid body movements of functional domains to form the catalytically competent state. In addition, a homology model of the human enzyme in the closed state based on the structure of D. discoideum UMP/CMP kinase aids to rationalize the substrate specificity of the human enzyme. |
| doi_str_mv | 10.1074/jbc.M401989200 |
| format | Article |
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In addition, this kinase is an essential component of the activation cascade of medicinally relevant nucleoside analog prodrugs such as AraC, gemcitabine, and ddC. During the catalytic cycle the enzyme undergoes large conformational changes from open in the absence of substrates to closed in the presence of both phosphoryl donor and phosphoryl acceptor. Here we report the crystal structure of the substrate-free, open form of human UMP/CMP kinase. Comparison of the open structure with the closed state previously reported for the similar Dictyostelium discoideum UMP/CMP kinase reveals the conformational changes that occur upon substrate binding. We observe a classic example of induced fit where substrate-induced conformational changes in hinge residues result in rigid body movements of functional domains to form the catalytically competent state. In addition, a homology model of the human enzyme in the closed state based on the structure of D. discoideum UMP/CMP kinase aids to rationalize the substrate specificity of the human enzyme.</description><identifier>ISSN: 0021-9258</identifier><identifier>EISSN: 1083-351X</identifier><identifier>DOI: 10.1074/jbc.M401989200</identifier><identifier>PMID: 15163660</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Adenosine Triphosphate - metabolism ; Amino Acid Sequence ; Animals ; Binding Sites ; Cloning, Molecular ; Computer Simulation ; Crystallization ; Crystallography, X-Ray ; Dictyostelium - enzymology ; Dictyostelium discoideum ; Gene Expression ; Humans ; Models, Molecular ; Molecular Sequence Data ; Molecular Structure ; Nucleoside-Phosphate Kinase - chemistry ; Nucleoside-Phosphate Kinase - genetics ; Nucleoside-Phosphate Kinase - metabolism ; Protein Conformation ; Substrate Specificity ; Uridine Monophosphate - metabolism</subject><ispartof>The Journal of biological chemistry, 2004-08, Vol.279 (32), p.33882-33889</ispartof><rights>2004 © 2004 ASBMB. 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In addition, this kinase is an essential component of the activation cascade of medicinally relevant nucleoside analog prodrugs such as AraC, gemcitabine, and ddC. During the catalytic cycle the enzyme undergoes large conformational changes from open in the absence of substrates to closed in the presence of both phosphoryl donor and phosphoryl acceptor. Here we report the crystal structure of the substrate-free, open form of human UMP/CMP kinase. Comparison of the open structure with the closed state previously reported for the similar Dictyostelium discoideum UMP/CMP kinase reveals the conformational changes that occur upon substrate binding. We observe a classic example of induced fit where substrate-induced conformational changes in hinge residues result in rigid body movements of functional domains to form the catalytically competent state. In addition, a homology model of the human enzyme in the closed state based on the structure of D. discoideum UMP/CMP kinase aids to rationalize the substrate specificity of the human enzyme.</description><subject>Adenosine Triphosphate - metabolism</subject><subject>Amino Acid Sequence</subject><subject>Animals</subject><subject>Binding Sites</subject><subject>Cloning, Molecular</subject><subject>Computer Simulation</subject><subject>Crystallization</subject><subject>Crystallography, X-Ray</subject><subject>Dictyostelium - enzymology</subject><subject>Dictyostelium discoideum</subject><subject>Gene Expression</subject><subject>Humans</subject><subject>Models, Molecular</subject><subject>Molecular Sequence Data</subject><subject>Molecular Structure</subject><subject>Nucleoside-Phosphate Kinase - chemistry</subject><subject>Nucleoside-Phosphate Kinase - genetics</subject><subject>Nucleoside-Phosphate Kinase - metabolism</subject><subject>Protein Conformation</subject><subject>Substrate Specificity</subject><subject>Uridine Monophosphate - metabolism</subject><issn>0021-9258</issn><issn>1083-351X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2004</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkE1P3DAURa2KCoaPbZcoC9RdBvvZcewdVdRCVUZFAiR2luO8MEYTh9oJFf--rmYkVoi3eZtzr64OIV8YXTJai_On1i1XgjKtNFD6iSwYVbzkFXvYIwtKgZUaKnVADlN6ovmEZvvkgFVMcinpglzczm2aop2w9KGbHXZFM4Z-jIOd_BjspmjWNjxiKnworubBhuJ-dXPerG6KXz7YhMfkc283CU92_4jc__h-11yV178vfzbfrksnBJ1KLVrRMa6cVYpyCy5PrmTfta3UAEArB8Cd47LFqhZgNdYdoLU98toyK_gR-brtfY7jnxnTZAafHG42NuA4JyNlLRmt9IcgMKiBqSqDyy3o4phSxN48Rz_Y-GoYNf_lmizXvMnNgdNd89wO2L3hO5sZONsCa_-4_usjmtaPbo2DgVobDoZzpSBjaoth9vXiMZrkPIbsPkfcZLrRvzfhH3CWkh4</recordid><startdate>20040806</startdate><enddate>20040806</enddate><creator>Segura-Peña, Dario</creator><creator>Sekulic, Nikolina</creator><creator>Ort, Stephan</creator><creator>Konrad, Manfred</creator><creator>Lavie, Arnon</creator><general>Elsevier Inc</general><general>American Society for Biochemistry and Molecular Biology</general><scope>6I.</scope><scope>AAFTH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>M7N</scope><scope>7X8</scope></search><sort><creationdate>20040806</creationdate><title>Substrate-induced Conformational Changes in Human UMP/CMP Kinase</title><author>Segura-Peña, Dario ; Sekulic, Nikolina ; Ort, Stephan ; Konrad, Manfred ; Lavie, Arnon</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c440t-94b4d138ca8803a2c01956fdbb6922205c223cc36be5742a9e7d2eaafe37a1a43</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2004</creationdate><topic>Adenosine Triphosphate - metabolism</topic><topic>Amino Acid Sequence</topic><topic>Animals</topic><topic>Binding Sites</topic><topic>Cloning, Molecular</topic><topic>Computer Simulation</topic><topic>Crystallization</topic><topic>Crystallography, X-Ray</topic><topic>Dictyostelium - enzymology</topic><topic>Dictyostelium discoideum</topic><topic>Gene Expression</topic><topic>Humans</topic><topic>Models, Molecular</topic><topic>Molecular Sequence Data</topic><topic>Molecular Structure</topic><topic>Nucleoside-Phosphate Kinase - chemistry</topic><topic>Nucleoside-Phosphate Kinase - genetics</topic><topic>Nucleoside-Phosphate Kinase - metabolism</topic><topic>Protein Conformation</topic><topic>Substrate Specificity</topic><topic>Uridine Monophosphate - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Segura-Peña, Dario</creatorcontrib><creatorcontrib>Sekulic, Nikolina</creatorcontrib><creatorcontrib>Ort, Stephan</creatorcontrib><creatorcontrib>Konrad, Manfred</creatorcontrib><creatorcontrib>Lavie, Arnon</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>MEDLINE - Academic</collection><jtitle>The Journal of biological chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Segura-Peña, Dario</au><au>Sekulic, Nikolina</au><au>Ort, Stephan</au><au>Konrad, Manfred</au><au>Lavie, Arnon</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Substrate-induced Conformational Changes in Human UMP/CMP Kinase</atitle><jtitle>The Journal of biological chemistry</jtitle><addtitle>J Biol Chem</addtitle><date>2004-08-06</date><risdate>2004</risdate><volume>279</volume><issue>32</issue><spage>33882</spage><epage>33889</epage><pages>33882-33889</pages><issn>0021-9258</issn><eissn>1083-351X</eissn><abstract>Human UMP/CMP kinase plays a crucial role in supplying precursors for nucleic acid synthesis by catalyzing the conversion of UMP, CMP, and dCMP into their diphosphate form. 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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Alma/SFX Local Collection |
| subjects | Adenosine Triphosphate - metabolism Amino Acid Sequence Animals Binding Sites Cloning, Molecular Computer Simulation Crystallization Crystallography, X-Ray Dictyostelium - enzymology Dictyostelium discoideum Gene Expression Humans Models, Molecular Molecular Sequence Data Molecular Structure Nucleoside-Phosphate Kinase - chemistry Nucleoside-Phosphate Kinase - genetics Nucleoside-Phosphate Kinase - metabolism Protein Conformation Substrate Specificity Uridine Monophosphate - metabolism |
| title | Substrate-induced Conformational Changes in Human UMP/CMP Kinase |
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