The domain within your query sequence starts at position 71 and ends at position 132; the E-value for the HOX domain shown below is 3.08e-2.

KEKTRLRAPPNATLEHFYQTSGKQPKQVEVDLLSRQSGLSGRQVERWFRRRRNQDRPSLL
KK

HOX

Homeodomain

• SMART accession number: SM00389
• Description: DNA-binding factors that are involved in the transcriptional regulation of key developmental processes
• Interpro abstract (IPR001356):

  The homeobox domain or homeodomain was first identified in a number of drosophila homeotic and segmentation proteins, but is now known to be well-conserved in many other animals, including vertebrates [ (PUBMED:2568852) (PUBMED:1357790) ]. Hox genes encode homeodomain-containing transcriptional regulators that operate differential genetic programs along the anterior-posterior axis of animal bodies [ (PUBMED:12445403) ]. The domain binds DNA through a helix-turn-helix (HTH) structure. The HTH motif is characterised by two alpha-helices, which make intimate contacts with the DNA and are joined by a short turn. The second helix binds to DNA via a number of hydrogen bonds and hydrophobic interactions, which occur between specific side chains and the exposed bases and thymine methyl groups within the major groove of the DNA. The first helix helps to stabilise the structure.

  The motif is very similar in sequence and structure in a wide range of DNA-binding proteins (e.g., cro and repressor proteins, homeotic proteins, etc.). One of the principal differences between HTH motifs in these different proteins arises from the stereo-chemical requirement for glycine in the turn which is needed to avoid steric interference of the beta-carbon with the main chain: for cro and repressor proteins the glycine appears to be mandatory, while for many of the homeotic and other DNA-binding proteins the requirement is relaxed.

• GO function: DNA binding (GO:0003677)

There are 130113 HOX domains in 120724 proteins in SMART's nrdb database.

Cellular role (predicted cellular role)

Cellular role: transcription
Binding / catalysis: DNA-binding

Literature (relevant references for this domain)

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

• Aravind L, Koonin EV
• The U box is a modified RING finger - a common domain in ubiquitination.
• Curr Biol. 2000; 10: 1324-1324

• Vershon AK
• Protein interactions of homeodomain proteins.
• Curr Opin Biotechnol. 1996; 7: 392-6

Homeodomain proteins are conserved DNA-binding factors that are involved in the transcriptional regulation of key developmental processes. Many homeodomain proteins require additional cofactors to bind with high affinity and specificity to their DNA sites. The recent structural determinations and biochemical analysis of several multimeric complexes have provided a better understanding of how protein interactions influence the DNA-binding activity of homeodomain proteins.

• Wolberger C
• Homeodomain interactions.
• Curr Opin Struct Biol. 1996; 6: 62-8

Homeodomain proteins play key roles in development and gene regulation in eukaryotes. Past structural studies have focused on the binding of monomeric homeodomains to DNA, but two recent structures have revealed how homeodomains bind DNA as multimers. The structures of the Drosophila Paired homodimer and the yeast a1/alpha2 heterodimer bound to DNA, along with a high-resolution study of a Drosophila eve-DNA complex, have deepened our understanding of how homeodomains locate their DNA targets.

• Xu W, Rould MA, Jun S, Desplan C, Pabo CO
• Crystal structure of a paired domain-DNA complex at 2.5 A resolution reveals structural basis for Pax developmental mutations.
• Cell. 1995; 80: 639-50

The 2.5 A resolution structure of a cocrystal containing the paired domain from the Drosophila paired (prd) protein and a 15 bp site shows structurally independent N-terminal and C-terminal subdomains. Each of these domains contains a helical region resembling the homeodomain and the Hin recombinase. The N-terminal domain makes extensive DNA contacts, using a novel beta turn motif that binds in the minor groove and a helix-turn-helix unit with a docking arrangement surprisingly similar to that of the lambda repressor. The C-terminal domain is not essential for prd binding and does not contact the optimized site. All known developmental missense mutations in the paired box of mammalian Pax genes map to the N-terminal subdomain, and most of them are found at the protein-DNA interface.

• Gehring WJ, Affolter M, Burglin T
• Homeodomain proteins.
• Annu Rev Biochem. 1994; 63: 487-526

• Gehring WJ et al.
• Homeodomain-DNA recognition.
• Cell. 1994; 78: 211-23

• Ghysen A
• Origins of segment periodicity.
• Nature. 1990; 344: 297-8

• Kissinger CR, Liu BS, Martin-Blanco E, Kornberg TB, Pabo CO
• Crystal structure of an engrailed homeodomain-DNA complex at 2.8 A resolution: a framework for understanding homeodomain-DNA interactions.
• Cell. 1990; 63: 579-90

The crystal structure of a complex containing the engrailed homeodomain and a duplex DNA site has been determined at 2.8 A resolution and refined to a crystallographic R factor of 24.4%. In this complex, two separate regions of the 61 amino acid polypeptide contact a TAAT subsite. An N-terminal arm fits into the minor groove, and the side chains of Arg-3 and Arg-5 make contacts near the 5' end of this "core consensus" binding site. An alpha helix fits into the major groove, and the side chains of IIe-47 and Asn-51 contact base pairs near the 3' end of the TAAT site. This "recognition helix" is part of a structurally conserved helix-turn-helix unit, but these helices are longer than the corresponding helices in the lambda repressor, and the relationship between the helix-turn-helix unit and the DNA is significantly different.

• Landschulz WH, Johnson PF, McKnight SL
• The leucine zipper: a hypothetical structure common to a new class of DNA binding proteins.
• Science. 1988; 240: 1759-64

A 30-amino-acid segment of C/EBP, a newly discovered enhancer binding protein, shares notable sequence similarity with a segment of the cellular Myc transforming protein. Display of these respective amino acid sequences on an idealized alpha helix revealed a periodic repetition of leucine residues at every seventh position over a distance covering eight helical turns. The periodic array of at least four leucines was also noted in the sequences of the Fos and Jun transforming proteins, as well as that of the yeast gene regulatory protein, GCN4. The polypeptide segments containing these periodic arrays of leucine residues are proposed to exist in an alpha-helical conformation, and the leucine side chains extending from one alpha helix interdigitate with those displayed from a similar alpha helix of a second polypeptide, facilitating dimerization. This hypothetical structure is referred to as the "leucine zipper," and it may represent a characteristic property of a new category of DNA binding proteins.

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

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

Protein	Disease
Homeobox protein MSX-1 (P28360) (SMART)	OMIM:142983: Hypodontia, autosomal dominant OMIM:106600: Hypodontia with orofacial cleft OMIM:106600:
Homeobox protein TGIF1 (Q15583) (SMART)	OMIM:142946: Holoprosencephaly-4 OMIM:602630: Holoprosencephaly-4 OMIM:142946:
Pituitary-specific positive transcription factor 1 (P28069) (SMART)	OMIM:173110: Pituitary hormone deficiency, combined
Paired box protein Pax-3 (P23760) (SMART)	OMIM:193500: Waardenburg syndrome, type I ; Waardenburg syndrome, type III OMIM:148820: Rhabdomyosarcoma, alveolar OMIM:268220: Craniofacial-deafness-hand syndrome OMIM:122880:
Homeobox protein SIX3 (O95343) (SMART)	OMIM:157170: Holoprosencephaly-2 OMIM:603714: Holoprosencephaly-2 OMIM:157170:
Homeobox protein prophet of Pit-1 (O75360) (SMART)	OMIM:601538: Pituitary hormone deficiency, combined
Pancreas/duodenum homeobox protein 1 (P52945) (SMART)	OMIM:600733: Pancreatic agenesis OMIM:260370: MODY, type IV
Homeobox expressed in ES cells 1 (Q9UBX0) (SMART)	OMIM:601802: Septooptic dysplasia OMIM:182230:
Homeobox protein MSX-2 (P35548) (SMART)	OMIM:123101: Craniosynostosis, type 2 OMIM:604757: Parietal foramina 1 OMIM:168500: OMIM:168500: Parietal foramina
Homeobox protein aristaless-like 4 (Q9H161) (SMART)	OMIM:168500: Parietal foramina OMIM:605420: Parietal foramina 2 OMIM:168500:
LIM homeobox transcription factor 1-beta (O60663) (SMART)	OMIM:602575: Nail-patella syndrome OMIM:161200: Nail-patella syndrome with open-angle glaucoma OMIM:137750:
Cone-rod homeobox protein (O43186) (SMART)	OMIM:602225: Cone-rod retinal dystrophy-2 OMIM:120970: Leber congenital amaurosis due to defect in CRX OMIM:204000: Retinitis pigmentosa, late-onset dominant
Homeobox protein Nkx-2.5 (P52952) (SMART)	OMIM:600584: Atrial septal defect with atrioventricular conduction defects OMIM:108900:
POU domain, class 3, transcription factor 4 (P49335) (SMART)	OMIM:300039: Deafness, X-linked 3, conductive, with stapes fixation OMIM:304400:
Pituitary homeobox 2 (Q99697) (SMART)	OMIM:137600: Iridogoniodysgenesis syndrome OMIM:601542: Rieger syndrome OMIM:180500: Iridogoniodysgenesis syndrome-2 OMIM:137600:

Metabolism (metabolic pathways involving proteins which contain this domain)

% proteins involved	KEGG pathway ID	Description
73.47	map04950	Maturity onset diabetes of the young
8.16	map04930	Type II diabetes mellitus
8.16	map04350	TGF-beta signaling pathway
7.14	map05215	Prostate cancer
3.06	map04111	Cell cycle - yeast

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 HOX domain which could be assigned to a KEGG orthologous group, and not all proteins containing HOX 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 HOX domains in PDB

PDB code	Title
1ahd	DETERMINATION OF THE NMR SOLUTION STRUCTURE OF AN ANTENNAPEDIA HOMEODOMAIN-DNA COMPLEX
1akh	MAT A1/ALPHA2/DNA TERNARY COMPLEX
1apl	CRYSTAL STRUCTURE OF A MAT-ALPHA2 HOMEODOMAIN-OPERATOR COMPLEX SUGGESTS A GENERAL MODEL FOR HOMEODOMAIN-DNA INTERACTIONS
1au7	PIT-1 MUTANT/DNA COMPLEX
1b72	PBX1, HOMEOBOX PROTEIN HOX-B1/DNA TERNARY COMPLEX
1b8i	STRUCTURE OF THE HOMEOTIC UBX/EXD/DNA TERNARY COMPLEX
1bw5	THE NMR SOLUTION STRUCTURE OF THE HOMEODOMAIN OF THE RAT INSULIN GENE ENHANCER PROTEIN ISL-1, 50 STRUCTURES
1cqt	CRYSTAL STRUCTURE OF A TERNARY COMPLEX CONTAINING AN OCA-B PEPTIDE, THE OCT-1 POU DOMAIN, AND AN OCTAMER ELEMENT
1du0	ENGRAILED HOMEODOMAIN Q50A VARIANT DNA COMPLEX
1du6	SOLUTION STRUCTURE OF THE TRUNCATED PBX HOMEODOMAIN
1e3o	Crystal structure of Oct-1 POU dimer bound to MORE
1enh	STRUCTURAL STUDIES OF THE ENGRAILED HOMEODOMAIN
1f43	SOLUTION STRUCTURE OF THE MATA1 HOMEODOMAIN
1fjl	HOMEODOMAIN FROM THE DROSOPHILA PAIRED PROTEIN BOUND TO A DNA OLIGONUCLEOTIDE
1ftt	THYROID TRANSCRIPTION FACTOR 1 HOMEODOMAIN (RATTUS NORVEGICUS)
1ftz	NUCLEAR MAGNETIC RESONANCE SOLUTION STRUCTURE OF THE FUSHI TARAZU HOMEODOMAIN FROM DROSOPHILA AND COMPARISON WITH THE ANTENNAPEDIA HOMEODOMAIN
1gt0	Crystal structure of a POU/HMG/DNA ternary complex
1hdd	CRYSTAL STRUCTURE OF AN ENGRAILED HOMEODOMAIN-DNA COMPLEX AT 2.8 ANGSTROMS RESOLUTION: A FRAMEWORK FOR UNDERSTANDING HOMEODOMAIN-DNA INTERACTIONS
1hdp	SOLUTION STRUCTURE OF A POU-SPECIFIC HOMEODOMAIN: 3D-NMR STUDIES OF HUMAN B-CELL TRANSCRIPTION FACTOR OCT-2
1hf0	Crystal structure of the DNA-binding domain of Oct-1 bound to DNA as a dimer
1hom	DETERMINATION OF THE THREE-DIMENSIONAL STRUCTURE OF THE ANTENNAPEDIA HOMEODOMAIN FROM DROSOPHILA IN SOLUTION BY 1H NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY
1ic8	HEPATOCYTE NUCLEAR FACTOR 1A BOUND TO DNA : MODY3 GENE PRODUCT
1ig7	Msx-1 Homeodomain/DNA Complex Structure
1jgg	Even-skipped Homeodomain Complexed to AT-rich DNA
1k61	MATALPHA2 HOMEODOMAIN BOUND TO DNA
1le8	Crystal Structure of the MATa1/MATalpha2-3A Heterodimer Bound to DNA Complex
1lfb	THE X-RAY STRUCTURE OF AN ATYPICAL HOMEODOMAIN PRESENT IN THE RAT LIVER TRANSCRIPTION FACTOR LFB1(SLASH)HNF1 AND IMPLICATIONS FOR DNA BINDING
1lfu	NMR Solution Stucture of the Extended PBX Homeodomain Bound to DNA
1mh3	maltose binding-a1 homeodomain protein chimera, crystal form I
1mh4	maltose binding-a1 homeodomain protein chimera, crystal form II
1mnm	YEAST MATALPHA2/MCM1/DNA TERNARY TRANSCRIPTION COMPLEX CRYSTAL STRUCTURE
1nk2	VND/NK-2 HOMEODOMAIN/DNA COMPLEX, NMR, 20 STRUCTURES
1nk3	VND/NK-2 HOMEODOMAIN/DNA COMPLEX, NMR, MINIMIZED AVERAGE STRUCTURE
1o4x	TERNARY COMPLEX OF THE DNA BINDING DOMAINS OF THE OCT1 AND SOX2 TRANSCRIPTION FACTORS WITH A 19MER OLIGONUCLEOTIDE FROM THE HOXB1 REGULATORY ELEMENT
1ocp	SOLUTION STRUCTURE OF OCT3 POU-HOMEODOMAIN
1oct	CRYSTAL STRUCTURE OF THE OCT-1 POU DOMAIN BOUND TO AN OCTAMER SITE: DNA RECOGNITION WITH TETHERED DNA-BINDING MODULES
1p7i	CRYSTAL STRUCTURE OF ENGRAILED HOMEODOMAIN MUTANT K52A
1p7j	Crystal structure of engrailed homeodomain mutant K52E
1pog	SOLUTION STRUCTURE OF THE OCT-1 POU-HOMEO DOMAIN DETERMINED BY NMR AND RESTRAINED MOLECULAR DYNAMICS
1puf	Crystal Structure of HoxA9 and Pbx1 homeodomains bound to DNA
1qry	Homeobox protein VND (ventral nervous system defective protein)
1s7e	Solution structure of HNF-6
1san	THE DES(1-6)ANTENNAPEDIA HOMEODOMAIN: COMPARISON OF THE NMR SOLUTION STRUCTURE AND THE DNA BINDING AFFINITY WITH THE INTACT ANTENNAPEDIA HOMEODOMAIN
1uhs	Solution structure of mouse homeodomain-only protein HOP
1vnd	VND/NK-2 PROTEIN (HOMEODOMAIN), NMR
1wi3	Solution structure of the homeodomain of KIAA1034 protein
1x2m	Solution structure of the homeobox domain of mouse LAG1 longevity assurance homolog 6
1x2n	Solution structure of the homeobox domain of human homeobox protein PKNOX1
1yrn	CRYSTAL STRUCTURE OF THE MATA1/MATALPHA2 HOMEODOMAIN HETERODIMER BOUND TO DNA
1zq3	NMR Solution Structure of the Bicoid Homeodomain Bound to the Consensus DNA Binding Site TAATCC
1ztr	Solution structure of Engrailed homeodomain L16A mutant
2cqx	Solution structure of RSGI RUH-034, a homeodomain from mouse cDNA
2cra	Solution structure of the homeobox domain of human homeo box B13
2cue	Solution structure of the homeobox domain of the human paired box protein Pax-6
2cuf	Solution structure of the homeobox domain of the human hypothetical protein FLJ21616
2d5v	Crystal structure of HNF-6alpha DNA-binding domain in complex with the TTR promoter
2da1	Solution structure of the first homeobox domain of AT-binding transcription factor 1 (ATBF1)
2da2	Solution structure of the second homeobox domain of AT-binding transcription factor 1 (ATBF1)
2da3	Solution structure of the third homeobox domain of AT-binding transcription factor 1 (ATBF1)
2da4	Solution structure of the homeobox domain of the hypothetical protein, DKFZp686K21156
2da5	Solution structure of the second homeobox domain of Zinc fingers and homeoboxes protein 3 (Triple homeobox 1 protein)
2da6	Solution structure of the homeobox domain of Hepatocyte nuclear factor 1-beta (HNF-1beta)
2da7	Solution structure of the homeobox domain of Zinc finger homeobox protein 1b (Smad interacting protein 1)
2djn	The solution structure of the homeobox domain of human Homeobox protein DLX-5
2dmn	The solution structure of the homeobox domain of human homeobox protein TGIF2LX
2dmp	Solution structure of the third homeobox domain of Zinc fingers and homeoboxes protein 2
2dmq	Solution structure of the homeobox domain of LIM/homeobox protein Lhx9
2dms	Solution structure of the homeobox domain of Homeobox protein OTX2
2dmt	Solution structure of the homeobox domain of Homeobox protein BarH-like 1
2dmu	Solution structure of the homeobox domain of Homeobox protein goosecoid
2dn0	Solution structure of the second homeobox domain of human zinc fingers and homeoboxes protein 3
2e19	Solution structure of the homeobox domain from human NIL-2-A zinc finger protein, transcription factor 8
2e1o	Solution structure of RSGI RUH-028, a homeobox domain from human cDNA
2ecb	The solution structure of the third homeobox domain of human zinc fingers and homeoboxes protein
2ecc	Solution Structure of the second Homeobox Domain of Human Homeodomain Leucine Zipper-Encoding Gene (Homez)
2h1k	Crystal structure of the Pdx1 homeodomain in complex with DNA
2h8r	Hepatocyte Nuclear Factor 1b bound to DNA: MODY5 Gene Product
2hdd	ENGRAILED HOMEODOMAIN Q50K VARIANT DNA COMPLEX
2hi3	Solution structure of the homeodomain-only protein HOP
2hoa	STRUCTURE DETERMINATION OF THE ANTP(C39->S) HOMEODOMAIN FROM NUCLEAR MAGNETIC RESONANCE DATA IN SOLUTION USING A NOVEL STRATEGY FOR THE STRUCTURE CALCULATION WITH THE PROGRAMS DIANA, CALIBA, HABAS AND GLOMSA
2hos	Phage-Selected Homeodomain Bound to Unmodified DNA
2hot	Phage selected homeodomain bound to modified DNA
2jwt	Solution structure of Engrailed homeodomain WT
2k40	NMR structure of HESX-1 homeodomain double mutant R31L/E42L
2kt0	Solution structure of human stem cell transcription factor Nanog homeodomain fragment
2l7f	Solution Structure of the Pitx2 Homeodomain
2l7m	Solution Structure of the Pitx2 Homeodomain R24H mutant
2l7z	NMR Structure of A13 homedomain
2l9r	Solution NMR Structure of Homeobox domain of Homeobox protein Nkx-3.1 from homo sapiens, Northeast Structural Genomics Consortium Target HR6470A
2ld5	Solution NMR-derived complex structure of Hoxa13 DNA binding domain bound to DNA
2lfb	HOMEODOMAIN FROM RAT LIVER LFB1/HNF1 TRANSCRIPTION FACTOR, NMR, 20 STRUCTURES
2lk2	Solution NMR structure of homeobox domain (171-248) of human homeobox protein TGIF1, Northeast Structural Genomics Consortium Target HR4411B
2lkx	NMR structure of the homeodomain of Pitx2 in complex with a TAATCC DNA binding site
2lp0	The solution structure of homeodomain-protein complex
2ly9	Solution NMR Structure of Homeobox 2 Domain from Human ZHX1 repressor, Northeast Structural Genomics Consortium (NESG) Target HR7907F
2m0c	Solution NMR Structure of Homeobox Domain of Human ALX4, Northeast Structural Genomics Consortium (NESG) Target HR4490C
2m34	NMR Structure of the homeodomain transcription factor Gbx1 from Homo sapiens
2me0	NMR Structure of the homeodomain transcription factor Gbx1 from Homo sapiens solved in the presence of the DNA sequence CGACTAATTAGTCG
2me6	NMR Structure of the homeodomain transcription factor Gbx1 from Homo sapiens in complex with the DNA sequence CGACTAATTAGTCG
2mg4	2MG4
2mgq	2MGQ
2msy	2MSY
2mw8	2MW8
2n8g	2N8G
2p81	Engrailed homeodomain helix-turn-helix motif
2r5y	Structure of Scr/Exd complex bound to a consensus Hox-Exd site
2r5z	Structure of Scr/Exd complex bound to a DNA sequence derived from the fkh gene
2vi6	Crystal Structure of the Nanog Homeodomain
2xsd	Crystal Structure of the dimeric Oct-6 (Pou3f1) POU domain bound to palindromic MORE DNA
3a01	Crystal structure of Aristaless and Clawless homeodomains bound to DNA
3a02	Crystal structure of Aristaless homeodomain
3a03	Crystal structure of Hox11L1 homeodomain
3cmy	Structure of a homeodomain in complex with DNA
3d1n	Structure of human Brn-5 transcription factor in complex with corticotrophin-releasing hormone gene promoter
3hdd	ENGRAILED HOMEODOMAIN DNA COMPLEX
3k2a	Crystal structure of the homeobox domain of human homeobox protein Meis2
3l1p	POU protein:DNA complex
3lnq	Structure of Aristaless homeodomain in complex with DNA
3nar	Crystal structure of ZHX1 HD4 (zinc-fingers and homeoboxes protein 1, homeodomain 4)
3nau	Crystal structure of ZHX2 HD2 (zinc-fingers and homeoboxes protein 2, homeodomain 2)
3rkq	NKX2.5 Homeodomain dimer bound to ANF-242 DNA
3zob	Solution structure of chicken Engrailed 2 homeodomain
4cyc	4CYC
4egc	Crystal Structure of MBP-fused Human Six1 Bound to Human Eya2 Eya Domain
4j19	Structure of a novel telomere repeat binding protein bound to DNA
4ndj	4NDJ
4ndk	4NDK
4ndl	4NDL
4qtr	4QTR
4rbo	4RBO
4rdu	4RDU
4s0h	4S0H
4uus	4UUS
4uut	4UUT
4xic	4XIC
4xid	4XID
4xrm	4XRM
4xrs	4XRS
4zn8	4ZN8
5bng	5BNG
5edn	5EDN
5eea	5EEA
5eg0	5EG0
5ego	5EGO
5flv	5FLV
5jlw	5JLW
5jlx	5JLX
9ant	ANTENNAPEDIA HOMEODOMAIN-DNA COMPLEX

Links (links to other resources describing this domain)

• PROSITE: HOMEOBOX_2
• PFAM: homeobox
• INTERPRO: IPR001356