4tz4

X-ray diffraction
3.01Å resolution

Crystal Structure of Human Cereblon in Complex with DDB1 and Lenalidomide

Released:
Source organism: Homo sapiens
Entry authors: Chamberlain PP, Pagarigan B, Delker S, Leon B, Riley M

Function and Biology Details

Reactions catalysed:
(1a) an (RNA) containing cytidine = an (RNA)-3'-cytidine-2',3'-cyclophosphate + a 5'-hydroxy-ribonucleotide-3'-(RNA)
Acts on substrates that are at least partially unfolded. The cleavage site P1 residue is normally between a pair of hydrophobic residues, such as Val-|-Val
1-(5-phospho-beta-D-ribosyl)-ATP + diphosphate = ATP + 5-phospho-alpha-D-ribose 1-diphosphate
ATP + a protein = ADP + a phosphoprotein
N-(5-phospho-D-ribosyl)-anthranilate + diphosphate = anthranilate + 5-phospho-alpha-D-ribose 1-diphosphate
(1a) (2R,3S)-3-isopropylmalate = 2-isopropylmaleate + H(2)O
Cleavage of peptide bonds with very broad specificity.
4 Fe(2+) + 4 H(+) + O(2) = 4 Fe(3+) + 2 H(2)O
4 benzenediol + O(2) = 4 benzosemiquinone + 2 H(2)O
Preferential cleavage: hydrophobic, preferably aromatic, residues in P1 and P1' positions. Cleaves 1-Phe-|-Val-2, 4-Gln-|-His-5, 13-Glu-|-Ala-14, 14-Ala-|-Leu-15, 15-Leu-|-Tyr-16, 16-Tyr-|-Leu-17, 23-Gly-|-Phe-24, 24-Phe-|-Phe-25 and 25-Phe-|-Tyr-26 bonds in the B chain of insulin.
ATP + [biotin carboxyl-carrier protein]-biotin-N(6)-L-lysine + hydrogencarbonate- = ADP + phosphate + [biotin carboxyl-carrier protein]-carboxybiotin-N(6)-L-lysine
Random endo-hydrolysis of N-acetyl-beta-D-glucosaminide (1->4)-beta-linkages in chitin and chitodextrins
dCTP + 2 H(2)O = dUMP + diphosphate + NH(3)
TSAVLQ-|-SGFRK-NH(2) and SGVTFQ-|-GKFKK the two peptides corresponding to the two self-cleavage sites of the SARS 3C-like proteinase are the two most reactive peptide substrates. The enzyme exhibits a strong preference for substrates containing Gln at P1 position and Leu at P2 position.
Tuberculosinyl diphosphate + adenosine = 1-tuberculosinyladenosine + diphosphate
Mycoredoxin + ROOH = mycoredoxin disulfide + H(2)O + ROH
A [lipoyl-carrier protein]-N(6)-((R)-dihydrolipoyl)-L-lysine + ROOH = a [lipoyl-carrier protein]-N(6)-((R)-lipoyl)-L-lysine + H(2)O + ROH
An acyl-[acyl-carrier protein] + NAD(+) = a trans-2,3-dehydroacyl-[acyl-carrier protein] + NADH
ATP + succinate + CoA = ADP + phosphate + succinyl-CoA
5,10-methylenetetrahydrofolate + dUMP + NADPH = dTMP + tetrahydrofolate + NADP(+)
Preferential cleavage at the carboxyl of hydrophobic amino acids, but fails to cleave 15-Leu-|-Tyr-16, 16-Tyr-|-Leu-17 and 24-Phe-|-Phe-25 of insulin B chain. Activates trypsinogen, and degrades keratin.
A beta-lactam + H(2)O = a substituted beta-amino acid
Protein tyrosine phosphate + H(2)O = protein tyrosine + phosphate
2 bilirubin + O(2) = 2 biliverdin + 2 H(2)O
S-adenosyl-L-methionine + a 5'-(N(7)-methyl 5'-triphosphoguanosine)-(ribonucleotide)-[mRNA] = S-adenosyl-L-homocysteine + a 5'-(N(7)-methyl 5'-triphosphoguanosine)-(2'-O-methyl-ribonucleotide)-[mRNA]
[a protein]-serine/threonine phosphate + H(2)O = [a protein]-serine/threonine + phosphate
ATP + (R)-pantoate + beta-alanine = AMP + diphosphate + (R)-pantothenate
(S)-malate = fumarate + H(2)O
H(2)CO(3) = CO(2) + H(2)O
Acetyl-CoA + L-glutamate = CoA + N-acetyl-L-glutamate
ATP + thymidine = ADP + thymidine 5'-phosphate
A glutathione-S-conjugate + H(2)O = an (L-cysteinylglycine)-S-conjugate + L-glutamate
Thiol-dependent hydrolysis of ester, thioester, amide, peptide and isopeptide bonds formed by the C-terminal Gly of ubiquitin (a 76-residue protein attached to proteins as an intracellular targeting signal).
Nucleoside triphosphate + RNA(n) = diphosphate + RNA(n+1)
Hydrolyzes single-stranded DNA or mismatched double-stranded DNA and polynucleotides, releasing free uracil
Hydrolysis of (1->4)-beta-D-glucosidic linkages in cellulose and similar substrates, releasing cellobiose from the reducing ends of the chains.
5,6,7,8-tetrahydrofolate + NADP(+) = 7,8-dihydrofolate + NADPH
L-arginine + 2-oxoglutarate + O(2) = (3S)-3-hydroxy-L-arginine + succinate + CO(2)
CoA-(4'-phosphopantetheine) + apo-[acyl-carrier-protein] = adenosine 3',5'-bisphosphate + holo-[acyl-carrier-protein]
ATP + protein L-histidine = ADP + protein N-phospho-L-histidine
ATP + (R)-pantothenate = ADP + (R)-4'-phosphopantothenate
N(2)-acetyl-L-ornithine + L-glutamate = L-ornithine + N-acetyl-L-glutamate
D-erythro-1-(imidazol-4-yl)glycerol 3-phosphate = 3-(imidazol-4-yl)-2-oxopropyl phosphate + H(2)O
ATP + H(2)O + a folded polypeptide = ADP + phosphate + an unfolded polypeptide
Acetyl-CoA + malonyl-[acyl-carrier-protein] = acetoacetyl-[acyl-carrier-protein] + CoA + CO(2) 
ATP + H(2)O = ADP + phosphate
2-C-methyl-D-erythritol 4-phosphate + NADP(+) = 1-deoxy-D-xylulose 5-phosphate + NADPH
N-carbamoylputrescine + H(2)O = putrescine + CO(2) + NH(3)
ATP + acetyl-CoA + HCO(3)(-) = ADP + phosphate + malonyl-CoA
A (5-L-glutamyl)-peptide + an amino acid = a peptide + a 5-L-glutamyl amino acid
Release of N-terminal amino acids, preferentially methionine, from peptides and arylamides.
Succinyl-CoA + enzyme N(6)-(dihydrolipoyl)lysine = CoA + enzyme N(6)-(S-succinyldihydrolipoyl)lysine
D-galactose + O(2) = D-galacto-hexodialdose + H(2)O(2)
IMP + diphosphate = hypoxanthine + 5-phospho-alpha-D-ribose 1-diphosphate
dUTP + H(2)O = dUMP + diphosphate
(8S)-3',8-cyclo-7,8-dihydroguanosine 5'-triphosphate = cyclic pyranopterin phosphate + diphosphate
D-glycero-beta-D-manno-heptose 1-phosphate + ATP = ADP-D-glycero-beta-D-manno-heptose + diphosphate
Endonucleolytic cleavage to 5'-phosphomonoester.
Release of N-terminal proline from a peptide.
Release of an N-terminal amino acid, Xaa-|-Yaa-, in which Xaa is preferably Leu, but may be other amino acids including Pro although not Arg or Lys, and Yaa may be Pro. Amino acid amides and methyl esters are also readily hydrolyzed, but rates on arylamides are exceedingly low.
7,8-dihydroneopterin = 7,8-dihydromonapterin
1-haloalkane + H(2)O = a primary alcohol + halide
Selective cleavage of Gln-|-Gly bond in the poliovirus polyprotein. In other picornavirus reactions Glu may be substituted for Gln, and Ser or Thr for Gly.
Diphosphate + H(2)O = 2 phosphate
3'-end directed exonucleolytic cleavage of viral RNA-DNA hybrid
L-cystathionine + H(2)O = L-homocysteine + NH(3) + pyruvate
4 S-adenosyl-L-methionine + 2-((3S)-3-carboxy-3-aminopropyl)-L-histidine-[translation elongation factor 2] = 4 S-adenosyl-L-homocysteine + diphthine methyl ester-[translation elongation factor 2]
Hydrolysis of alpha-(2->3)-, alpha-(2->6)-, alpha-(2->8)- glycosidic linkages of terminal sialic acid residues in oligosaccharides, glycoproteins, glycolipids, colominic acid and synthetic substrates.
ATP + phenylacetate + CoA = AMP + diphosphate + phenylacetyl-CoA
Nitric oxide + H(2)O + ferricytochrome c = nitrite + ferrocytochrome c + 2 H(+)
NTP + H(2)O = NDP + phosphate
ATP + H(2)O + 4 H(+)(Side 1) = ADP + phosphate + 4 H(+)(Side 2)
L-alanine = D-alanine
(+)-muconolactone = 5-oxo-4,5-dihydrofuran-2-acetate
ATP + deamido-NAD(+) + L-glutamine + H(2)O = AMP + diphosphate + NAD(+) + L-glutamate
(3R)-3-hydroxyacyl-[acyl-carrier-protein] + NADP(+) = 3-oxoacyl-[acyl-carrier-protein] + NADPH
Isocitrate = succinate + glyoxylate
ATP + (R)-5-diphosphomevalonate = ADP + phosphate + isopentenyl diphosphate + CO(2)
2-carboxy-2,5-dihydro-5-oxofuran-2-acetate = cis,cis-butadiene-1,2,4-tricarboxylate
3-deoxy-D-manno-octulosonate 8-phosphate + H(2)O = 3-deoxy-D-manno-octulosonate + phosphate
ATP = 3',5'-cyclic AMP + diphosphate
6-hydroxymethyl-7,8-dihydropterin diphosphate + 4-aminobenzoate = diphosphate + dihydropteroate
L-fuculose 1-phosphate = glycerone phosphate + (S)-lactaldehyde
Autocatalytic release of the core protein from the N-terminus of the togavirus structural polyprotein by hydrolysis of a -Trp-|-Ser- bond.
Selective hydrolysis of -Xaa-Xaa-|-Yaa- bonds in which each of the Xaa can be either Arg or Lys and Yaa can be either Ser or Ala.
Autocatalytically cleaves itself from the polyprotein of the foot-and-mouth disease virus by hydrolysis of a Lys-|-Gly bond, but then cleaves host cell initiation factor eIF-4G at bonds -Gly-|-Arg- and -Lys-|-Arg-.
Preferential cleavage of -Tyr(16)-|-Leu- and -Phe(25)-|-Tyr-bonds of oxidized insulin B chain. Also acts on other substrates of less than 7 kDa such as insulin and glucagon.
5,10-methylenetetrahydrofolate + 3-methyl-2-oxobutanoate + H(2)O = tetrahydrofolate + 2-dehydropantoate
(1E,2Z)-3-hydroxy-5,9,17-trioxo-4,5:9,10-disecoandrosta-1(10),2-dien-4-oate + H(2)O = 3-((3aS,4S,7aS)-7a-methyl-1,5-dioxo-octahydro-1H-inden-4-yl)propanoate + (2Z,4Z)-2-hydroxyhexa-2,4-dienoate
ADP-alpha-D-glucose + D-glucose 6-phosphate = ADP + alpha,alpha-trehalose 6-phosphate
Endohydrolysis of RNA in RNA/DNA hybrids. Three different cleavage modes: 1. sequence-specific internal cleavage of RNA. Human immunodeficiency virus type 1 and Moloney murine leukemia virus enzymes prefer to cleave the RNA strand one nucleotide away from the RNA-DNA junction. 2. RNA 5'-end directed cleavage 13-19 nucleotides from the RNA end. 3. DNA 3'-end directed cleavage 15-20 nucleotides away from the primer terminus.
Deoxynucleoside triphosphate + DNA(n) = diphosphate + DNA(n+1)
A primary alcohol + 2 cytochrome c(L) = an aldehyde + 2 reduced cytochrome c(L) + 2 H(+)
Reduced plastocyanin + oxidized ferredoxin + light = oxidized plastocyanin + reduced ferredoxin
L-alanine + H(2)O + NAD(+) = pyruvate + NH(3) + NADH
ATP + 6-hydroxymethyl-7,8-dihydropterin = AMP + 6-hydroxymethyl-7,8-dihydropterin diphosphate
Hydrolysis of the -Gly-|-Gly- bond in the pentaglycine inter-peptide link joining staphylococcal cell wall peptidoglycans.
A (3R)-3-hydroxyacyl-[acyl-carrier-protein] + a UDP-3-O-((3R)-hydroxyacyl)-alpha-D-glucosamine = a UDP-2-N,3-O-bis((3R)-3-hydroxyacyl)-alpha-D-glucosamine + a holo-[acyl-carrier-protein]
7,8-dihydroneopterin + O(2) = 7,8-dihydroxanthopterin + formate + glycolaldehyde
ATP + pyridoxal = ADP + pyridoxal 5'-phosphate
(1R,6R)-6-hydroxy-2-succinylcyclohexa-2,4-diene-1-carboxylate = 2-succinylbenzoate + H(2)O
Selective cleavage of Tyr-|-Gly bond in picornavirus polyprotein.
(+)-muconolactone = cis,cis-muconate
7,8-dihydroneopterin = 6-hydroxymethyl-7,8-dihydropterin + glycolaldehyde
AMP + H(2)O = D-ribose 5-phosphate + adenine
Preferential cleavage: (Ac)(2)-L-Lys-D-Ala-|-D-Ala. Also transpeptidation of peptidyl-alanyl moieties that are N-acyl substituents of D-alanine.
A 2'-deoxyribonucleoside 5'-monophosphate + H(2)O = a 2'-deoxyribonucleoside + phosphate
An acyl-[acyl-carrier-protein] + S-adenosyl-L-methionine = [acyl-carrier-protein] + S-methyl-5'-thioadenosine + an N-acyl-L-homoserine lactone
NH(3) + 2 H(2)O + 6 ferricytochrome c = nitrite + 6 ferrocytochrome c + 7 H(+)
(GlcNAc-(1->4)-Mur2Ac(oyl-L-Ala-gamma-D-Glu-L-Lys-D-Ala-D-Ala))(n)-diphosphoundecaprenol + GlcNAc-(1->4)-Mur2Ac(oyl-L-Ala-gamma-D-Glu-L-Lys-D-Ala-D-Ala)-diphosphoundecaprenol = (GlcNAc-(1->4)-Mur2Ac(oyl-L-Ala-gamma-D-Glu-L-Lys-D-Ala-D-Ala))(n+1)-diphosphoundecaprenol + undecaprenyl diphosphate
2,6-dioxo-6-phenylhexa-3-enoate + H(2)O = benzoate + 2-oxopent-4-enoate
The C-O-P bond 3' to the apurinic or apyrimidinic site in DNA is broken by a beta-elimination reaction, leaving a 3'-terminal unsaturated sugar and a product with a terminal 5'-phosphate
Release of an N-terminal amino acid, preferentially leucine, but not glutamic or aspartic acids.
Biochemical function:
Cellular component:

Structure analysis Details

Assembly composition:
hetero dimer (preferred)
Entry contents:
2 distinct polypeptide molecules
Macromolecules (2 distinct):
DNA damage-binding protein 1 Chain: A
Molecule details ›
Chain: A
Length: 1146 amino acids
Theoretical weight: 127.88 KDa
Source organism: Homo sapiens
Expression system: Spodoptera frugiperda
UniProt:
  • Canonical: Q16531 (Residues: 2-1140; Coverage: 100%)
Gene names: DDB1, XAP1
Sequence domains:
Structure domains:
Protein cereblon Chain: C
Molecule details ›
Chain: C
Length: 381 amino acids
Theoretical weight: 43.87 KDa
Source organism: Homo sapiens
Expression system: Spodoptera frugiperda
UniProt:
  • Canonical: Q96SW2 (Residues: 48-428; Coverage: 86%)
Gene names: AD-006, CRBN
Sequence domains: ATP-dependent protease La (LON) substrate-binding domain
Structure domains:

Ligands and Environments

2 bound ligands:
No modified residues

Experiments and Validation Details

Entry percentile scores
X-ray source: CLSI BEAMLINE 08ID-1
Spacegroup: P212121
Unit cell:
a: 71.862Å b: 129.117Å c: 198.677Å
α: 90° β: 90° γ: 90°
R-values:
R R work R free
0.205 0.202 0.271
Expression system: Spodoptera frugiperda