4LC9

Structural Basis for Regulation of Human Glucokinase by Glucokinase Regulatory Protein

External Resource: Annotation

Domain Annotation: SCOP2 Classification
Domain Annotation: ECOD Classification
Domain Annotation: CATH
Protein Family Annotation
Gene Ontology: Gene Product Annotation
InterPro: Protein Family Classification
Pharos: Disease Associations

Domain Annotation: SCOP2 Classification SCOP2 Database Homepage

Chains	Type	Family Name	Domain Identifier	Family Identifier	Provenance Source (Version)
B	SCOP2B Superfamily	Actin-like ATPases	8035412	3000092	SCOP2B (2022-06-29)
B	SCOP2B Superfamily	Actin-like ATPases	8035413	3000092	SCOP2B (2022-06-29)

Domain Annotation: ECOD Classification ECOD Database Homepage

Chains	Family Name	Domain Identifier	Architecture	Possible Homology	Homology	Topology	Family	Provenance Source (Version)
A	PF20741	e4lc9A2	A: alpha arrays	X: RuvA-C	H: C-terminal lid domain of glucokinase regulatory protein (From Topology)	T: C-terminal lid domain of glucokinase regulatory protein	F: PF20741	ECOD (1.6)
A	PF22198	e4lc9A4	A: a/b three-layered sandwiches	X: Flavodoxin-like	H: Ribosomal protein S2/SIS domain (From Topology)	T: Ribosomal protein S2/SIS domain	F: PF22198	ECOD (1.6)
A	PF22645	e4lc9A3	A: a/b three-layered sandwiches	X: Flavodoxin-like	H: Ribosomal protein S2/SIS domain (From Topology)	T: Ribosomal protein S2/SIS domain	F: PF22645	ECOD (1.6)
B	PF00349	e4lc9B1	A: mixed a+b and a/b	X: Ribonuclease H-like	H: Ribonuclease H-like (From Topology)	T: Ribonuclease H-like	F: PF00349	ECOD (1.6)
B	PF03727	e4lc9B2	A: mixed a+b and a/b	X: Ribonuclease H-like	H: Ribonuclease H-like (From Topology)	T: Ribonuclease H-like	F: PF03727	ECOD (1.6)

Domain Annotation: CATH CATH Database Homepage

Chain	Domain	Class	Architecture	Topology	Homology	Provenance Source (Version)
A	3.40.50.10490	Alpha Beta	3-Layer(aba) Sandwich	Rossmann fold	Glucose-6-phosphate isomerase like protein	CATH (4.3.0)
B	3.40.367.20	Alpha Beta	3-Layer(aba) Sandwich	Hexokinase	domain 1	CATH (4.3.0)
B	3.30.420.40	Alpha Beta	2-Layer Sandwich	Nucleotidyltransferase	domain 5	CATH (4.3.0)

Protein Family Annotation Pfam Database Homepage

Chains	Accession	Name	Description	Comments	Source
A	PF20741	C-terminal lid domain of glucokinase regulatory protein (GKRP-like_C)	C-terminal lid domain of glucokinase regulatory protein	This domain is found at the C terminus of Glucokinase regulatory protein (GKRP) from animals and N-acetylmuramic acid 6-phosphate etherase (MurQ) from bacteria. GKRP binds Glucokinase (GK) mainly through hydrophobic interactions, functioning as an al ...	This domain is found at the C terminus of Glucokinase regulatory protein (GKRP) from animals and N-acetylmuramic acid 6-phosphate etherase (MurQ) from bacteria. GKRP binds Glucokinase (GK) mainly through hydrophobic interactions, functioning as an allosteric switch in blood glucose control by the liver [1]. GKRP is trilobal in shape, consisting of two topologically identical sugar isomerase (SIS) domains (Pfam:PF01380 and Pfam:PF13580) capped by an alpha helical C-terminal domain (this entry). The Lid domain consists of a bundle of seven alpha helices with a core that shows a UBA-like fold [2]. MurQ, which also shows a SIS domain, plays a key role in the peptidoglycane recycling pathway. Its crystal structure shows each monomer have an alpha-beta-alpha sandwich fold commonly found in regulatory proteins controlling the expression of genes involved in the synthesis of phosphosugars. The C-terminal domain of this protein (this entry) is comprised of five alpha helices [4].	Domain
B	PF03727	Hexokinase (Hexokinase_2)	Hexokinase	Hexokinase (EC:2.7.1.1) contains two structurally similar domains represented by this family and Pfam:PF00349. Some members of the family have two copies of each of these domains.	Domain
B	PF00349	Hexokinase (Hexokinase_1)	Hexokinase	Hexokinase (EC:2.7.1.1) contains two structurally similar domains represented by this family and Pfam:PF03727. Some members of the family have two copies of each of these domains.	Domain

Gene Ontology: Gene Product Annotation Gene Ontology Database Homepage

Chains	Polymer	Molecular Function	Biological Process	Cellular Component
A	Glucokinase regulatory protein	protein binding binding protein domain specific binding ion binding anion binding carbohydrate derivative binding fructose-6-phosphate binding small molecule binding enzyme regulator activity molecular function inhibitor activity molecular function regulator activity enzyme inhibitor activity kinase inhibitor activity kinase regulator activity protein binding binding protein domain specific binding ion binding anion binding carbohydrate derivative binding fructose-6-phosphate binding small molecule binding enzyme regulator activity molecular function inhibitor activity molecular function regulator activity enzyme inhibitor activity kinase inhibitor activity kinase regulator activity carbohydrate binding kinase binding enzyme binding glucose sensor activity small molecule sensor activity	cellular homeostasis chemical homeostasis homeostatic process glucose homeostasis carbohydrate homeostasis intracellular chemical homeostasis intracellular glucose homeostasis triglyceride homeostasis acylglycerol homeostasis lipid homeostasis protein localization establishment of protein localization cellular localization nitrogen compound transport cellular homeostasis chemical homeostasis homeostatic process glucose homeostasis carbohydrate homeostasis intracellular chemical homeostasis intracellular glucose homeostasis triglyceride homeostasis acylglycerol homeostasis lipid homeostasis protein localization establishment of protein localization cellular localization nitrogen compound transport nucleocytoplasmic transport transport nuclear transport organic substance transport intracellular transport protein localization to nucleus establishment of localization localization import into nucleus establishment of protein localization to organelle protein transport cellular macromolecule localization macromolecule localization protein localization to organelle establishment of localization in cell protein import into nucleus cellular process intracellular protein transport response to hexose response to organic substance response to monosaccharide response to carbohydrate response to stimulus response to chemical response to oxygen-containing compound response to fructose response to glucose monosaccharide metabolic process carbohydrate metabolic process organic substance metabolic process hexose metabolic process small molecule metabolic process metabolic process primary metabolic process glucose metabolic process organic cyclic compound metabolic process organonitrogen compound metabolic process urate metabolic process purine-containing compound metabolic process carbohydrate derivative metabolic process	membrane-bounded organelle intracellular organelle intracellular anatomical structure mitochondrion organelle cytoplasm cellular anatomical entity intracellular membrane-bounded organelle cytosol nucleus membrane-enclosed lumen intracellular organelle lumen nucleoplasm organelle lumen membrane-bounded organelle intracellular organelle intracellular anatomical structure mitochondrion organelle cytoplasm cellular anatomical entity intracellular membrane-bounded organelle cytosol nucleus membrane-enclosed lumen intracellular organelle lumen nucleoplasm organelle lumen nuclear lumen
B	Glucokinase	glucokinase activity carbohydrate kinase activity kinase activity hexokinase activity transferase activity catalytic activity phosphotransferase activity, alcohol group as acceptor transferase activity, transferring phosphorus-containing groups binding adenyl ribonucleotide binding nucleotide binding purine ribonucleotide binding purine ribonucleoside triphosphate binding nucleoside phosphate binding glucokinase activity carbohydrate kinase activity kinase activity hexokinase activity transferase activity catalytic activity phosphotransferase activity, alcohol group as acceptor transferase activity, transferring phosphorus-containing groups binding adenyl ribonucleotide binding nucleotide binding purine ribonucleotide binding purine ribonucleoside triphosphate binding nucleoside phosphate binding ion binding purine nucleotide binding organic cyclic compound binding anion binding adenyl nucleotide binding ATP binding heterocyclic compound binding carbohydrate derivative binding ribonucleotide binding small molecule binding fructokinase activity glucose binding monosaccharide binding carbohydrate binding mannokinase activity glucose sensor activity small molecule sensor activity	cellular homeostasis chemical homeostasis homeostatic process glucose homeostasis carbohydrate homeostasis intracellular chemical homeostasis intracellular glucose homeostasis monosaccharide metabolic process carbohydrate metabolic process catabolic process hexose catabolic process carbohydrate catabolic process hexose metabolic process primary metabolic process cellular homeostasis chemical homeostasis homeostatic process glucose homeostasis carbohydrate homeostasis intracellular chemical homeostasis intracellular glucose homeostasis monosaccharide metabolic process carbohydrate metabolic process catabolic process hexose catabolic process carbohydrate catabolic process hexose metabolic process primary metabolic process organic substance metabolic process glucose catabolic process small molecule metabolic process metabolic process monosaccharide catabolic process small molecule catabolic process organic substance catabolic process glucose metabolic process regulation of cellular process regulation of generation of precursor metabolites and energy positive regulation of macromolecule biosynthetic process regulation of primary metabolic process positive regulation of glycogen metabolic process positive regulation of metabolic process regulation of small molecule metabolic process organic substance biosynthetic process positive regulation of macromolecule metabolic process regulation of biological process carbohydrate biosynthetic process cellular metabolic process regulation of cellular metabolic process positive regulation of glucose metabolic process positive regulation of glycogen biosynthetic process biosynthetic process energy reserve metabolic process regulation of macromolecule biosynthetic process macromolecule metabolic process positive regulation of carbohydrate metabolic process regulation of glycogen metabolic process regulation of metabolic process regulation of glycogen biosynthetic process glucan biosynthetic process energy derivation by oxidation of organic compounds cellular biosynthetic process regulation of glucan biosynthetic process positive regulation of biological process positive regulation of cellular metabolic process regulation of polysaccharide metabolic process polysaccharide metabolic process glucan metabolic process positive regulation of biosynthetic process regulation of carbohydrate metabolic process regulation of glucose metabolic process positive regulation of cellular process regulation of biosynthetic process polysaccharide biosynthetic process glycogen metabolic process biological regulation generation of precursor metabolites and energy regulation of macromolecule metabolic process glycogen biosynthetic process macromolecule biosynthetic process regulation of cellular biosynthetic process regulation of polysaccharide biosynthetic process cellular process regulation of carbohydrate biosynthetic process positive regulation of small molecule metabolic process positive regulation of cellular biosynthetic process organophosphate metabolic process phosphate-containing compound metabolic process carbohydrate derivative metabolic process glucose 6-phosphate metabolic process phosphorus metabolic process ribonucleotide catabolic process pyridine nucleotide catabolic process oxoacid metabolic process organophosphate catabolic process nucleoside phosphate catabolic process organic acid metabolic process regulation of ATP metabolic process nucleobase-containing compound metabolic process regulation of purine nucleotide catabolic process glycolytic process regulation of nucleotide metabolic process regulation of phosphate metabolic process pyridine-containing compound metabolic process regulation of nucleobase-containing compound metabolic process purine ribonucleotide catabolic process pyridine nucleotide metabolic process nucleoside phosphate metabolic process organonitrogen compound catabolic process nicotinamide nucleotide metabolic process regulation of carbohydrate catabolic process pyruvate metabolic process purine nucleoside diphosphate metabolic process purine-containing compound catabolic process nucleotide metabolic process regulation of purine nucleotide metabolic process nucleobase-containing compound catabolic process organic cyclic compound metabolic process nucleoside diphosphate metabolic process purine nucleoside diphosphate catabolic process nucleoside diphosphate catabolic process regulation of nucleotide catabolic process regulation of phosphorus metabolic process nucleoside triphosphate metabolic process monocarboxylic acid metabolic process purine ribonucleotide metabolic process pyridine-containing compound catabolic process ribose phosphate metabolic process ATP metabolic process purine nucleotide metabolic process ribonucleotide metabolic process nucleobase-containing small molecule metabolic process purine ribonucleoside triphosphate metabolic process ribonucleoside diphosphate metabolic process ribonucleoside diphosphate catabolic process nucleotide catabolic process ribonucleoside triphosphate metabolic process purine nucleoside triphosphate metabolic process purine nucleotide catabolic process carbohydrate derivative catabolic process organonitrogen compound metabolic process ADP catabolic process carboxylic acid metabolic process regulation of catabolic process regulation of glycolytic process organic cyclic compound catabolic process purine-containing compound metabolic process ADP metabolic process purine ribonucleoside diphosphate metabolic process purine ribonucleoside diphosphate catabolic process NADP metabolic process response to hexose response to organic substance response to monosaccharide response to carbohydrate response to stimulus response to glucose response to chemical response to oxygen-containing compound carbohydrate phosphorylation phosphorylation protein localization regulation of localization establishment of protein localization nitrogen compound transport cell communication localization cellular macromolecule localization regulation of biological quality regulation of peptide hormone secretion regulation of hormone levels organic substance transport establishment of protein localization to extracellular region protein secretion establishment of localization regulation of protein secretion regulation of secretion cellular localization regulation of hormone secretion regulation of protein localization regulation of peptide secretion transport signaling hormone secretion protein localization to extracellular region peptide secretion secretion by cell regulation of secretion by cell amide transport signal release regulation of signaling secretion regulation of transport regulation of peptide transport regulation of establishment of protein localization cell-cell signaling export from cell regulation of protein transport peptide transport protein transport regulation of cellular localization regulation of insulin secretion peptide hormone secretion macromolecule localization hormone transport regulation of cell communication insulin secretion cellular response to stimulus response to endogenous stimulus cellular response to leptin stimulus cellular response to endogenous stimulus cellular response to chemical stimulus response to hormone response to leptin cellular response to organic substance cellular response to hormone stimulus regulation of potassium ion transport regulation of monoatomic ion transport metal ion transport monoatomic ion transport potassium ion transport monoatomic cation transport regulation of metal ion transport calcium ion import calcium ion transport negative regulation of small molecule metabolic process negative regulation of biological process gluconeogenesis negative regulation of cellular metabolic process negative regulation of gluconeogenesis negative regulation of cellular process negative regulation of carbohydrate metabolic process small molecule biosynthetic process negative regulation of metabolic process monosaccharide biosynthetic process negative regulation of cellular biosynthetic process hexose biosynthetic process negative regulation of biosynthetic process regulation of gluconeogenesis cellular response to nitrogen compound response to organonitrogen compound response to peptide hormone cellular response to peptide hormone stimulus response to nitrogen compound cellular response to oxygen-containing compound cellular response to organonitrogen compound response to insulin cellular response to insulin stimulus NADH regeneration glucose catabolic process to pyruvate NADH metabolic process canonical glycolysis NAD metabolic process glycolytic process through glucose-6-phosphate NAD catabolic process glycolytic process through fructose-6-phosphate positive regulation of cell communication positive regulation of establishment of protein localization positive regulation of insulin secretion positive regulation of peptide hormone secretion positive regulation of protein localization positive regulation of secretion by cell positive regulation of protein transport positive regulation of hormone secretion positive regulation of secretion positive regulation of peptide secretion positive regulation of protein secretion positive regulation of transport positive regulation of signaling	membrane-bounded organelle intracellular organelle intracellular anatomical structure mitochondrion organelle cytoplasm cellular anatomical entity intracellular membrane-bounded organelle cytosol nucleus membrane-enclosed lumen intracellular organelle lumen nucleoplasm organelle lumen membrane-bounded organelle intracellular organelle intracellular anatomical structure mitochondrion organelle cytoplasm cellular anatomical entity intracellular membrane-bounded organelle cytosol nucleus membrane-enclosed lumen intracellular organelle lumen nucleoplasm organelle lumen nuclear lumen

InterPro: Protein Family Classification InterPro Database Homepage

Chains	Accession	Name	Type
A	IPR005486	Glucokinase regulatory protein, conserved site	Conserved Site
A	IPR046348	SIS domain superfamily	Homologous Superfamily
A	IPR040190	N-acetylmuramic acid 6-phosphate etherase/glucokinase regulatory protein	Family
A	IPR001347	SIS domain	Domain
B	IPR043129	ATPase, nucleotide binding domain	Homologous Superfamily
B	IPR022673	Hexokinase, C-terminal	Domain
B	IPR019807	Hexokinase, binding site	Binding Site
B	IPR001312	Hexokinase	Family
B	IPR022672	Hexokinase, N-terminal	Domain

Pharos: Disease Associations Pharos Homepage Annotation

Chains	Drug Target	Associated Disease
B	Pharos: P35557	maturity-onset diabetes of the young type 2 diabetes mellitus hyperglycemia hyperinsulinism due to glucokinase deficiency permanent neonatal diabetes mellitus Congenital Hyperinsulinism maturity-onset diabetes of the young type 2 permanent neonatal diabetes mellitus 1 hyperinsulinemic hypoglycemia hyperinsulinism inborn errors of metabolism medulloblastoma acquired metabolic disease diabetes mellitus hyperinsulinemic hypoglycemia, familial, 2 maturity-onset diabetes of the young type 2 diabetes mellitus hyperglycemia hyperinsulinism due to glucokinase deficiency permanent neonatal diabetes mellitus Congenital Hyperinsulinism maturity-onset diabetes of the young type 2 permanent neonatal diabetes mellitus 1 hyperinsulinemic hypoglycemia hyperinsulinism inborn errors of metabolism medulloblastoma acquired metabolic disease diabetes mellitus hyperinsulinemic hypoglycemia, familial, 2 intellectual disability metabolic syndrome X congenital isolated hyperinsulinism gestational diabetes hypoglycemia neonatal diabetes mellitus carpal tunnel syndrome primitive neuroectodermal tumor DEND syndrome hyperinsulinemic hypoglycemia, familial, 1

RCSB PDB Core Operations are funded by the U.S. National Science Foundation (DBI-2321666), the US Department of Energy (DE-SC0019749), and the National Cancer Institute, National Institute of Allergy and Infectious Diseases, and National Institute of General Medical Sciences of the National Institutes of Health under grant R01GM133198.