CYCLIN

domain present in cyclins, TFIIB and Retinoblastoma

• SMART accession number: SM00385
• Description: A helical domain present in cyclins and TFIIB (twice) and Retinoblastoma (once). A protein recognition domain functioning in cell-cycle and transcription control.
• Interpro abstract (IPR013763):

  This cyclin-like domain is found in cyclins, but it is also found as the core domain in transcription factor IIB (TFIIB) and in the retinoblastoma tumour suppressor. It consists of a duplication of a fold consisting of 5 helices, one of them surrounded by the others.

There are 6385 CYCLIN domains in 4315 proteins in SMART's nrdb database.

Cellular role (predicted cellular role)

Cellular role: transcription

Literature (relevant references for this domain)

Primary literature is listed below; Automatically-derived, secondary literature is also avaliable.

• Endicott JA, Noble ME
• Structural principles in cell-cycle control: beyond the CDKs.
• Structure. 1998; 6: 535-41

Retinoblastoma protein (Rb) interacts with cyclin-dependent kinases and regulates the transcription of genes necessary for progression through the S phase of the cell cycle. Clues to the atomic mechanisms involved are offered by the structure of the two pocket regions of Rb in complex with a short peptide from a viral oncoprotein. Structures of cyclins, Rb and TFIIB reveal that a common motif occurs in proteins regulating three consecutive events of cell-cycle control.

• Lee JO, Russo AA, Pavletich NP
• Structure of the retinoblastoma tumour-suppressor pocket domain bound to a peptide from HPV E7.
• Nature. 1998; 391: 859-65

The pocket domain of the retinoblastoma (Rb) tumour suppressor is central to Rb function, and is frequently inactivated by the binding of the human papilloma virus E7 oncoprotein in cervical cancer. The crystal structure of the Rb pocket bound to a nine-residue E7 peptide containing the LxCxE motif, shared by other Rb-binding viral and cellular proteins, shows that the LxCxE peptide binds a highly conserved groove on the B-box portion of the pocket; the A-box portion appears to be required for the stable folding of the B box. Also highly conserved is the extensive A-B interface, suggesting that it may be an additional protein-binding site. The A and B boxes each contain the cyclin-fold structural motif, with the LxCxE-binding site on the B-box cyclin fold being similar to a Cdk2-binding site of cyclin A and to a TBP-binding site of TFIIB.

• Kim HY, Cho Y
• Structural similarity between the pocket region of retinoblastoma tumour suppressor and the cyclin-box.
• Nat Struct Biol. 1997; 4: 390-5

The pocket region of retinoblastoma tumour suppressor (Rb) is essential for tumour suppressing activity. The Rb pocket is primarily composed of two domains, A and B. We have determined the X-ray crystal structure of domain A (residues 378-562) at 2.3 A resolution. Domain A consists of nine alpha-helices. The overall arrangement of helices in domain A is remarkably similar to the cyclin-box folds found in the crystal structures of cyclin A and TFIIB. This structure, along with domain B which is predicted to be homologous to the cyclin-box, suggests that the Rb pocket is composed of two cyclin-box fold domains. We present the structural/functional features of the Rb pocket, and the potential binding region for cellular or viral proteins within domain A.

• Noble ME, Endicott JA, Brown NR, Johnson LN
• The cyclin box fold: protein recognition in cell-cycle and transcription control.
• Trends Biochem Sci. 1997; 22: 482-7

Regulation of both the cell cycle and gene transcription is essential for orderly progression of cell growth and division. Recent results on the structures of two cyclins, cyclin A and cyclin H, and two transcription factor mediator proteins, TFIIB and the A pocket region of the retinoblastoma tumour suppressor protein (Rb), show that they share domains with a strikingly similar alpha-helical topology, despite remote sequence identity.

• Bagby S, Kim S, Maldonado E, Tong KI, Reinberg D, Ikura M
• Solution structure of the C-terminal core domain of human TFIIB: similarity to cyclin A and interaction with TATA-binding protein.
• Cell. 1995; 82: 857-67

TFIIB is an essential component of the machinery that transcribes protein-coding genes. The three-dimensional structure of the human TFIIB core domain (TFIIBc) has been determined using multidimensional heteronuclear magnetic resonance spectroscopy. The molecule consists of two direct repeats that adopt similar alpha-helical folds, conferring pseudo-twofold symmetry. An extensive, central basic surface including an amphipathic alpha helix is critical to the function of TFIIB as a bridge between the TBP-promoter complex and RNA polymerase II and associated general and regulatory transcription factors. Similarities between the TFIIBc and cyclin A folds indicate that elements of the eukaryotic cell cycle control apparatus evolved from more fundamental transcriptional control components, demonstrating a link between the transcription and cell cycle molecular machineries.

• Gibson TJ, Thompson JD, Blocker A, Kouzarides T
• Evidence for a protein domain superfamily shared by the cyclins, TFIIB and RB/p107.
• Nucleic Acids Res. 1994; 22: 946-52

Cyclins, TFIIB and RB play major roles in cell cycle and/or gene regulation. Earlier work has suggested common ancestry for the TFIIB repeats and RB pocket B which share 20% sequence identity. We now report that database searches with profiles based on a multiple alignment of cyclin core regions (the 'cyclin box') detect the TFIIB repeats with equivalent scores to divergent cyclins. Several features of the sequences support the notion of common ancestry: e.g. cyclins A/B, C and D share approximately 20-30% identity but each have approximately 15-20% identity with vertebrate TFIIB, showing that conserved cyclin features underlie the match. These results suggest the presence of a domain superfamily, which we term the TR domain, in nuclear regulatory proteins belonging to the TFIIB, cyclin and RB families, that has been duplicated many times during eukaryotic evolution. The TR domain appears to function in protein-protein interactions.

Disease (disease genes where sequence variants are found in this domain)

SwissProt sequences and OMIM curated human diseases associated with missense mutations within the CYCLIN domain.

Protein	Disease
Retinoblastoma-associated protein (P06400) (SMART)	OMIM:180200: Retinoblastoma ; Osteosarcoma OMIM:259500: Bladder cancer OMIM:109800: Pinealoma with bilateral retinoblastoma

Metabolism (metabolic pathways involving proteins which contain this domain)

% proteins involved	KEGG pathway ID	Description
17.79	map04110	Cell cycle
13.09	map03022	Basal transcription factors
12.25	map04115	p53 signaling pathway
6.21	map04914	Progesterone-mediated oocyte maturation
5.03	map05222	Small cell lung cancer
5.03	map05215	Prostate cancer
3.86	map04630	Jak-STAT signaling pathway
3.86	map04111	Cell cycle - yeast
3.86	map04510	Focal adhesion
3.86	map04310	Wnt signaling pathway
2.68	map05219	Bladder cancer
2.68	map05212	Pancreatic cancer
2.68	map05220	Chronic myeloid leukemia
2.68	map05214	Glioma
2.68	map05223	Non-small cell lung cancer
2.68	map05218	Melanoma
2.52	map04350	TGF-beta signaling pathway
1.34	map05216	Thyroid cancer
1.34	map05210	Colorectal cancer
1.34	map05213	Endometrial cancer
1.34	map05221	Acute myeloid leukemia
0.50	map00562	Inositol phosphate metabolism
0.50	map00632	Benzoate degradation via CoA ligation
0.17	map03020	RNA polymerase

This information is based on mapping of SMART genomic protein database to KEGG orthologous groups. Percentage points are related to the number of proteins with CYCLIN domain which could be assigned to a KEGG orthologous group, and not all proteins containing CYCLIN domain. Please note that proteins can be included in multiple pathways, ie. the numbers above will not always add up to 100%.

Structure (3D structures containing this domain)

3D Structures of CYCLIN domains in PDB

PDB code	Title
1ais	Tata-binding protein/transcription factor (ii)b/tata-box complex from pyrococcus woesei
1bu2	X-ray structure of a viral cyclin from herpesvirus saimiri
1c9b	Crystal structure of a human tbp core domain-human tfiib core domain complex bound to an extended, modified adenoviral major late promoter (admlp)
1d3u	Tata-binding protein/transcription factor (ii)b/bre+tata- box complex from pyrococcus woesei
1e9h	Thr 160 phosphorylated cdk2 - human cyclin a3 complex with the inhibitor indirubin-5-sulphonate bound
1f5q	Crystal structure of murine gamma herpesvirus cyclin complexed to human cyclin dependent kinase 2
1fin	Cyclin a-cyclin-dependent kinase 2 complex
1fvv	The structure of cdk2/cyclin a in complex with an oxindole inhibitor
1g3n	Structure of a p18(ink4c)-cdk6-k-cyclin ternary complex
1gh6	Retinoblastoma pocket complexed with sv40 large t antigen
1gux	Rb pocket bound to e7 lxcxe motif
1gy3	Pcdk2/cyclin a in complex with mgadp, nitrate and peptide substrate
1h1p	Structure of human thr160-phospho cdk2/cyclin a complexed with the inhibitor nu2058
1h1q	Structure of human thr160-phospho cdk2/cyclin a complexed with the inhibitor nu6094
1h1r	Structure of human thr160-phospho cdk2/cyclin a complexed with the inhibitor nu6086
1h1s	Structure of human thr160-phospho cdk2/cyclin a complexed with the inhibitor nu6102
1h24	Cdk2/cyclin a in complex with a 9 residue recruitment peptide from e2f
1h25	Cdk2/cyclin a in complex with an 11-residue recruitment peptide from retinoblastoma-associated protein
1h26	Cdk2/cyclin a in complex with an 11-residue recruitment peptide from p53
1h27	Cdk2/cyclin a in complex with an 11-residue recruitment peptide from p27
1h28	Cdk2/cyclin a in complex with an 11-residue recruitment peptide from p107
1jkw	Structure of cyclin mcs2
1jow	Crystal structure of a complex of human cdk6 and a viral cyclin
1jst	Phosphorylated cyclin-dependent kinase-2 bound to cyclin a
1jsu	P27(kip1)/cyclin a/cdk2 complex
1kxu	Cyclin h, a positive regulatory subunit of cdk activating kinase
1n4m	Structure of rb tumor suppressor bound to the transactivation domain of e2f-2
1o9k	Crystal structure of the retinoblastoma tumour suppressor protein bound to e2f peptide
1ogu	Structure of human thr160-phospho cdk2/cyclin a complexed with a 2-arylamino-4-cyclohexylmethyl-5-nitroso-6-aminopyrimidine inhibitor
1oi9	Structure of human thr160-phospho cdk2/cyclin a complexed with a 6-cyclohexylmethyloxy-2-anilino-purine inhibitor
1oiu	Structure of human thr160-phospho cdk2/cyclin a complexed with a 6-cyclohexylmethyloxy-2-anilino-purine inhibitor
1oiy	Structure of human thr160-phospho cdk2/cyclin a complexed with a 6-cyclohexylmethyloxy-2-anilino-purine inhibitor
1okv	Cyclin a binding groove inhibitor h-arg-arg-leu-ile-phe-nh2
1okw	Cyclin a binding groove inhibitor ac-arg-arg-leu-asn- (m-cl-phe)-nh2
1ol1	Cyclin a binding groove inhibitor h-cit-cit-leu-ile- (p-f-phe)-nh2
1ol2	Cyclin a binding groove inhibitor h-arg-arg-leu-asn- (p-f-phe)-nh2
1p5e	The strucure of phospho-cdk2/cyclin a in complex with the inhibitor 4,5,6,7-tetrabromobenzotriazole (tbs)
1pkd	The crystal structure of ucn-01 in complex with phospho- cdk2/cyclin a
1qmz	Phosphorylated cdk2-cyclyin a-substrate peptide complex
1tfb	Nmr studies of human general transcription factor tfiib: dynamics and interaction with vp16 activation domain, 20 structures
1urc	Cyclin a binding groove inhibitor ace-arg-lys-leu- phe-gly
1vin	Bovine cyclin a3
1vol	Tfiib (human core domain)/tbp (a.thaliana)/tata element ternary complex
1vyw	Structure of cdk2/cyclin a with pnu-292137
1w98	The structural basis of cdk2 activation by cyclin e
1xo2	Crystal structure of a human cyclin-dependent kinase 6 complex with a flavonol inhibitor, fisetin
1zp2	Structure of the mediator subunit cyclin c
2b9r	Crystal structure of human cyclin b1
2bkz	Structure of cdk2-cyclin a with pha-404611
2bpm	Structure of cdk2-cyclin a with pha-630529
2c4g	Structure of cdk2-cyclin a with pha-533514
2c5n	Differential binding of inhibitors to active and inactive cdk2 provides insights for drug design
2c5o	Differential binding of inhibitors to active and inactive cdk2 provides insights for drug design
2c5v	Differential binding of inhibitors to active and inactive cdk2 provides insights for drug design
2c5x	Differential binding of inhibitors to active and inactive cdk2 provides insights for drug design
2c6t	Crystal structure of the human cdk2 complexed with the triazolopyrimidine inhibitor
2cch	The crystal structure of cdk2 cyclin a in complex with a substrate peptide derived from cdc modified with a gamma- linked atp analogue
2cci	Crystal structure of phospho-cdk2 cyclin a in complex with a peptide containing both the substrate and recruitment sites of cdc6
2cjm	Mechanism of cdk inhibition by active site phosphorylation: cdk2 y15p t160p in complex with cyclin a structure
2euf	X-ray structure of human cdk6-vcyclin in complex with the inhibitor pd0332991
2f2c	X-ray structure of human cdk6-vcyclinwith the inhibitor aminopurvalanol
2g9x	Structure of thr 160 phosphorylated cdk2/cyclin a in complex with the inhibitor nu6271
2i40	Cdk2/cyclin a complexed with a thiophene carboxamide inhibitor
2i53	Crystal structure of cyclin k
2ivx	Crystal structure of human cyclin t2 at 1.8 a resolution (casp target)
2iw6	Structure of human thr160-phospho cdk2-cyclin a complexed with a bisanilinopyrimidine inhibitor
2iw8	Structure of human thr160-phospho cdk2-cyclin a f82h-l83v- h84d mutant with an o6-cyclohexylmethylguanine inhibitor
2iw9	Structure of human thr160-phospho cdk2-cyclin a complexed with a bisanilinopyrimidine inhibitor
2jgz	Crystal structure of phospho-cdk2 in complex with cyclin b
2phg	Model for vp16 binding to tfiib
2pk2	Cyclin box structure of the p-tefb subunit cyclin t1 derived from a fusion complex with eiav tat
2r7g	Structure of the retinoblastoma protein pocket domain in complex with adenovirus e1a cr1 domain
2uue	Replace: a strategy for iterative design of cyclin binding groove inhibitors
2uzb	Crystal structure of human cdk2 complexed with a thiazolidinone inhibitor
2uzd	Crystal structure of human cdk2 complexed with a thiazolidinone inhibitor
2uze	Crystal structure of human cdk2 complexed with a thiazolidinone inhibitor
2uzl	Crystal structure of human cdk2 complexed with a thiazolidinone inhibitor
2v22	Replace: a strategy for iterative design of cyclin binding groove inhibitors
2w2h	Structural basis of transcription activation by the cyclin t1-tat-tar rna complex from eiav
2w96	Crystal structure of cdk4 in complex with a d-type cyclin
2w99	Crystal structure of cdk4 in complex with a d-type cyclin
2w9f	Crystal structure of cdk4 in complex with a d-type cyclin
2w9z	Crystal structure of cdk4 in complex with a d-type cyclin
2wev	Truncation and optimisation of peptide inhibitors of cdk2, cyclin a through structure guided design
2wfy	Truncation and optimisation of peptide inhibitors of cdk2, cyclin a through structure guided design
2wha	Truncation and optimisation of peptide inhibitors of cdk2, cyclin a through structure guided design
2whb	Truncation and optimisation of peptide inhibitors of cdk2, cyclin a through structure guided design
2wih	Structure of cdk2-cyclin a with pha-848125
2wip	Structure of cdk2-cyclin a complexed with 8-anilino-1- methyl-4,5-dihydro-1h-pyrazolo[4,3-h] quinazoline-3- carboxylic acid
3bht	Structure of phosphorylated thr160 cdk2/cyclin a in complex with the inhibitor meriolin 3
3bhu	Structure of phosphorylated thr160 cdk2/cyclin a in complex with the inhibitor meriolin 5
3bhv	Structure of phosphorylated thr160 cdk2/cyclin a in complex with the inhibitor variolin b
3blh	Crystal structure of human cdk9/cyclint1
3blq	Crystal structure of human cdk9/cyclint1 in complex with atp
3blr	Crystal structure of human cdk9/cyclint1 in complex with flavopiridol
3ddp	Structure of phosphorylated thr160 cdk2/cyclin a in complex with the inhibitor cr8
3ddq	Structure of phosphorylated thr160 cdk2/cyclin a in complex with the inhibitor roscovitine
3dog	Structure of thr 160 phosphorylated cdk2/cyclin a in complex with the inhibitor n-&-n1
3eid	Cdk2/cyclina complexed with a pyrazolopyridazine inhibitor
3ej1	Cdk2/cyclina complexed with a pyrazolopyridazine inhibitor
3eoc	Cdk2/cyclina complexed with a imidazo triazin-2-amine
3f5x	Cdk-2-cyclin complex with indazole inhibitor 9 bound at its active site
3g33	Crystal structure of cdk4/cyclin d3
3k7a	Crystal structure of an rna polymerase ii-tfiib complex

Links (links to other resources describing this domain)

• PFAM: cyclin
• INTERPRO: IPR013763
• PROSITE: CYCLINS