PDBsum entry 1hyr

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protein Protein-protein interface(s) links
Immune system PDB id
Protein chains
128 a.a. *
275 a.a. *
Waters ×46
* Residue conservation analysis
PDB id:
Name: Immune system
Title: Crystal structure of human mica in complex with natural killer cell receptor nkg2d
Structure: Nkg2-d type ii integral membrane protein. Chain: b, a. Fragment: extracellular domain (residues 80 to 216). Synonym: nkg2d. Engineered: yes. Mhc class i chain-related protein a. Chain: c. Fragment: extracellular domain (residues 1 to 274). Synonym: mic-a, mic, perb11.
Source: Homo sapiens. Human. Organism_taxid: 9606. Cellular_location: cell surface. Gene: nkg2d. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008. Gene: mica-001. Expressed in: escherichia coli.
Biol. unit: Dodecamer (from PQS)
2.70Å     R-factor:   0.227     R-free:   0.282
Authors: P.Li,R.K.Strong
Key ref:
P.Li et al. (2001). Complex structure of the activating immunoreceptor NKG2D and its MHC class I-like ligand MICA. Nat Immunol, 2, 443-451. PubMed id: 11323699 DOI: 10.1038/87757
21-Jan-01     Release date:   23-May-01    
Go to PROCHECK summary

Protein chains
Pfam   ArchSchema ?
P26718  (NKG2D_HUMAN) -  NKG2-D type II integral membrane protein
216 a.a.
128 a.a.
Protein chain
Pfam   ArchSchema ?
Q29983  (MICA_HUMAN) -  MHC class I polypeptide-related sequence A
383 a.a.
275 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     membrane   1 term 
  Biological process     immune response   2 terms 
  Biochemical function     carbohydrate binding     1 term  


DOI no: 10.1038/87757 Nat Immunol 2:443-451 (2001)
PubMed id: 11323699  
Complex structure of the activating immunoreceptor NKG2D and its MHC class I-like ligand MICA.
P.Li, D.L.Morris, B.E.Willcox, A.Steinle, T.Spies, R.K.Strong.
The major histocompatibility complex (MHC) class I homolog, MICA, is a stress-inducible ligand for NKG2D, a C-type lectin-like activating immunoreceptor. The crystal structure of this ligand-receptor complex that we report here reveals an NKG2D homodimer bound to a MICA monomer in an interaction that is analogous to that seen in T cell receptor-MHC class I protein complexes. Similar surfaces on each NKG2D monomer interact with different surfaces on either the alpha1 or alpha2 domains of MICA. The binding interactions are large in area and highly complementary. The central section of the alpha2-domain helix, disordered in the structure of MICA alone, is ordered in the complex and forms part of the NKG2D interface. The extensive flexibility of the interdomain linker of MICA is shown by its altered conformation when crystallized alone or in complex with NKG2D.

Literature references that cite this PDB file's key reference

  PubMed id Reference
21262824 B.Xu, J.C.Pizarro, M.A.Holmes, C.McBeth, V.Groh, T.Spies, and R.K.Strong (2011).
Crystal structure of a gammadelta T-cell receptor specific for the human MHC class I homolog MICA.
  Proc Natl Acad Sci U S A, 108, 2414-2419.
PDB code: 3omz
20831445 I.Azimi, J.W.Wong, and P.J.Hogg (2011).
Control of mature protein function by allosteric disulfide bonds.
  Antioxid Redox Signal, 14, 113-126.  
21091928 L.Q.Ge, T.Jiang, J.Zhao, Z.T.Chen, F.Zhou, and B.Xia (2011).
Upregulated mRNA expression of major histocompatibility complex class I chain-related gene A in colon and activated natural killer cells of Chinese patients with ulcerative colitis.
  J Dig Dis, 12, 82-89.  
21444796 M.G.Joyce, P.Tran, M.A.Zhuravleva, J.Jaw, M.Colonna, and P.D.Sun (2011).
Crystal structure of human natural cytotoxicity receptor NKp30 and identification of its ligand binding site.
  Proc Natl Acad Sci U S A, 108, 6223-6228.  
21422170 Y.Li, Q.Wang, and R.A.Mariuzza (2011).
Structure of the human activating natural cytotoxicity receptor NKp30 bound to its tumor cell ligand B7-H6.
  J Exp Med, 208, 703-714.  
20032175 H.P.Su, K.Singh, A.G.Gittis, and D.N.Garboczi (2010).
The structure of the poxvirus A33 protein reveals a dimer of unique C-type lectin-like domains.
  J Virol, 84, 2502-2510.
PDB code: 3k7b
21179506 K.Köhler, S.Xiong, J.Brzostek, M.Mehrabi, P.Eissmann, A.Harrison, S.P.Cordoba, S.Oddos, V.Miloserdov, K.Gould, N.J.Burroughs, P.A.van der Merwe, and D.M.Davis (2010).
Matched sizes of activating and inhibitory receptor/ligand pairs are required for optimal signal integration by human natural killer cells.
  PLoS One, 5, e15374.  
20153697 M.K.Choy, and M.E.Phipps (2010).
MICA polymorphism: biology and importance in immunity and disease.
  Trends Mol Med, 16, 97.  
20068167 O.Ashiru, P.Boutet, L.Fernández-Messina, S.Agüera-González, J.N.Skepper, M.Valés-Gómez, and H.T.Reyburn (2010).
Natural killer cell cytotoxicity is suppressed by exposure to the human NKG2D ligand MICA*008 that is shed by tumor cells in exosomes.
  Cancer Res, 70, 481-489.  
20090832 S.Müller, G.Zocher, A.Steinle, and T.Stehle (2010).
Structure of the HCMV UL16-MICB complex elucidates select binding of a viral immunoevasin to diverse NKG2D ligands.
  PLoS Pathog, 6, e1000723.
PDB code: 2wy3
19604395 C.L.Mayer, W.K.Snyder, M.A.Swietlicka, A.D.Vanschoiack, C.R.Austin, and B.J.McFarland (2009).
Size-exclusion chromatography can identify faster-associating protein complexes and evaluate design strategies.
  BMC Res Notes, 2, 135.  
19147769 J.D.Wu, C.L.Atteridge, X.Wang, T.Seya, and S.R.Plymate (2009).
Obstructing shedding of the immunostimulatory MHC class I chain-related gene B prevents tumor formation.
  Clin Cancer Res, 15, 632-640.  
  20061825 J.Steigerwald, T.Raum, S.Pflanz, R.Cierpka, S.Mangold, D.Rau, P.Hoffmann, M.Kvesic, C.Zube, S.Linnerbauer, J.Lumsden, M.Sriskandarajah, P.Kufer, P.A.Baeuerle, and J.Volkland (2009).
Human IgG1 antibodies antagonizing activating receptor NKG2D on natural killer cells.
  MAbs, 1, 115-127.  
19424970 M.Wittenbrink, J.Spreu, and A.Steinle (2009).
Differential NKG2D binding to highly related human NKG2D ligands ULBP2 and RAET1G is determined by a single amino acid in the alpha2 domain.
  Eur J Immunol, 39, 1642-1651.  
19689730 N.Stern-Ginossar, and O.Mandelboim (2009).
An integrated view of the regulation of NKG2D ligands.
  Immunology, 128, 1-6.  
19353249 R.Kopp, J.Glas, U.Lau-Werner, E.D.Albert, and E.H.Weiss (2009).
Association of MICA-TM and MICB C1_2_A microsatellite polymorphisms with tumor progression in patients with colorectal cancer.
  J Clin Immunol, 29, 545-554.  
19615970 X.Wang, A.D.Lundgren, P.Singh, D.R.Goodlett, S.R.Plymate, and J.D.Wu (2009).
An six-amino acid motif in the alpha3 domain of MICA is the cancer therapeutic target to inhibit shedding.
  Biochem Biophys Res Commun, 387, 476-481.  
19604491 Y.Li, M.Hofmann, Q.Wang, L.Teng, L.K.Chlewicki, H.Pircher, and R.A.Mariuzza (2009).
Structure of natural killer cell receptor KLRG1 bound to E-cadherin reveals basis for MHC-independent missing self recognition.
  Immunity, 31, 35-46.
PDB codes: 3ff7 3ff8 3ff9
20477573 A.Falorni, A.Brozzetti, D.L.Torre, C.Tortoioli, and G.Gambelunghe (2008).
Association of genetic polymorphisms and autoimmune Addison's disease.
  Expert Rev Clin Immunol, 4, 441-456.  
18560379 B.A.Rabinovich, R.R.Ketchem, M.Wolfson, L.Goldstein, M.Skelly, and D.Cosman (2008).
A role for the MHC class I-like Mill molecules in nutrient metabolism and wound healing.
  Immunol Cell Biol, 86, 489-496.  
18448674 B.K.Kaiser, J.C.Pizarro, J.Kerns, and R.K.Strong (2008).
Structural basis for NKG2A/CD94 recognition of HLA-E.
  Proc Natl Acad Sci U S A, 105, 6696-6701.
PDB code: 3cii
18332182 E.J.Petrie, C.S.Clements, J.Lin, L.C.Sullivan, D.Johnson, T.Huyton, A.Heroux, H.L.Hoare, T.Beddoe, H.H.Reid, M.C.Wilce, A.G.Brooks, and J.Rossjohn (2008).
CD94-NKG2A recognition of human leukocyte antigen (HLA)-E bound to an HLA class I leader sequence.
  J Exp Med, 205, 725-735.
PDB code: 3cdg
18809410 K.Y.Kwong, S.Baskar, H.Zhang, C.L.Mackall, and C.Rader (2008).
Generation, affinity maturation, and characterization of a human anti-human NKG2D monoclonal antibody with dual antagonistic and agonistic activity.
  J Mol Biol, 384, 1143-1156.  
18426793 L.Deng, S.Cho, E.L.Malchiodi, M.C.Kerzic, J.Dam, and R.A.Mariuzza (2008).
Molecular architecture of the major histocompatibility complex class I-binding site of Ly49 natural killer cell receptors.
  J Biol Chem, 283, 16840-16849.
PDB codes: 3c8j 3c8k 3cad
  18768829 Q.J.Wang, K.Hanada, and J.C.Yang (2008).
Characterization of a novel nonclassical T cell clone with broad reactivity against human renal cell carcinomas.
  J Immunol, 181, 3769-3776.  
18957310 R.J.Duquesnoy, J.Mostecki, J.Hariharan, and I.Balazs (2008).
Structurally based epitope analysis of major histocompatibility complex class I-related chain A (MICA) antibody specificity patterns.
  Hum Immunol, 69, 826-832.  
18193361 S.J.Burgess, K.Maasho, M.Masilamani, S.Narayanan, F.Borrego, and J.E.Coligan (2008).
The NKG2D receptor: immunobiology and clinical implications.
  Immunol Res, 40, 18-34.  
18574582 S.L.Rogers, and J.Kaufman (2008).
High allelic polymorphism, moderate sequence diversity and diversifying selection for B-NK but not B-lec, the pair of lectin-like receptor genes in the chicken MHC.
  Immunogenetics, 60, 461-475.  
18544572 W.Cao, X.Xi, Z.Wang, L.Dong, Z.Hao, L.Cui, C.Ma, and W.He (2008).
Four novel ULBP splice variants are ligands for human NKG2D.
  Int Immunol, 20, 981-991.  
18309314 W.Held, and R.A.Mariuzza (2008).
Cis interactions of immunoreceptors with MHC and non-MHC ligands.
  Nat Rev Immunol, 8, 269-278.  
17216437 A.Averdam, S.Seelke, I.Grützner, C.Rosner, C.Roos, N.Westphal, C.Stahl-Hennig, V.Muppala, A.Schrod, U.Sauermann, R.Dressel, and L.Walter (2007).
Genotyping and segregation analyses indicate the presence of only two functional MIC genes in rhesus macaques.
  Immunogenetics, 59, 247-251.  
17614877 A.R.Mistry, and C.A.O'Callaghan (2007).
Regulation of ligands for the activating receptor NKG2D.
  Immunology, 121, 439-447.  
17495932 B.K.Kaiser, D.Yim, I.T.Chow, S.Gonzalez, Z.Dai, H.H.Mann, R.K.Strong, V.Groh, and T.Spies (2007).
Disulphide-isomerase-enabled shedding of tumour-associated NKG2D ligands.
  Nature, 447, 482-486.  
17690100 C.S.Lengyel, L.J.Willis, P.Mann, D.Baker, T.Kortemme, R.K.Strong, and B.J.McFarland (2007).
Mutations designed to destabilize the receptor-bound conformation increase MICA-NKG2D association rate and affinity.
  J Biol Chem, 282, 30658-30666.  
17911424 G.Gambelunghe, A.Brozzetti, M.Ghaderi, P.Candeloro, C.Tortoioli, and A.Falorni (2007).
MICA gene polymorphism in the pathogenesis of type 1 diabetes.
  Ann N Y Acad Sci, 1110, 92-98.  
17195078 I.Lionello, P.Mangia, L.Gattinoni, D.Pende, A.Cippone, M.Sensi, P.Rigatti, and C.Traversari (2007).
CD8(+) T lymphocytes isolated from renal cancer patients recognize tumour cells through an HLA- and TCR/CD3-independent pathway.
  Cancer Immunol Immunother, 56, 1065-1076.  
17285285 J.Birch, and S.A.Ellis (2007).
Complexity in the cattle CD94/NKG2 gene families.
  Immunogenetics, 59, 273-280.  
18083576 L.C.Sullivan, C.S.Clements, T.Beddoe, D.Johnson, H.L.Hoare, J.Lin, T.Huyton, E.J.Hopkins, H.H.Reid, M.C.Wilce, J.Kabat, F.Borrego, J.E.Coligan, J.Rossjohn, and A.G.Brooks (2007).
The heterodimeric assembly of the CD94-NKG2 receptor family and implications for human leukocyte antigen-E recognition.
  Immunity, 27, 900-911.
PDB code: 3bdw
17570210 M.Allez, V.Tieng, A.Nakazawa, X.Treton, V.Pacault, N.Dulphy, S.Caillat-Zucman, P.Paul, J.M.Gornet, C.Douay, S.Ravet, R.Tamouza, D.Charron, M.Lémann, L.Mayer, and A.Toubert (2007).
CD4+NKG2D+ T cells in Crohn's disease mediate inflammatory and cytotoxic responses through MICA interactions.
  Gastroenterology, 132, 2346-2358.  
16485126 R.Solana, J.G.Casado, E.Delgado, O.DelaRosa, J.Marín, E.Durán, G.Pawelec, and R.Tarazona (2007).
Lymphocyte activation in response to melanoma: interaction of NK-associated receptors and their ligands.
  Cancer Immunol Immunother, 56, 101-109.  
16931041 C.C.Chang, and S.Ferrone (2006).
NK cell activating ligands on human malignant cells: molecular and functional defects and potential clinical relevance.
  Semin Cancer Biol, 16, 383-392.  
16914326 J.D.Coudert, and W.Held (2006).
The role of the NKG2D receptor for tumor immunity.
  Semin Cancer Biol, 16, 333-343.  
16500675 K.Natarajan, A.Hicks, J.Mans, H.Robinson, R.Guan, R.A.Mariuzza, and D.H.Margulies (2006).
Crystal structure of the murine cytomegalovirus MHC-I homolog m144.
  J Mol Biol, 358, 157-171.
PDB code: 1u58
16737824 L.Deng, and R.A.Mariuzza (2006).
Structural basis for recognition of MHC and MHC-like ligands by natural killer cell receptors.
  Semin Immunol, 18, 159-166.  
16551255 M.G.Rudolph, R.L.Stanfield, and I.A.Wilson (2006).
How TCRs bind MHCs, peptides, and coreceptors.
  Annu Rev Immunol, 24, 419-466.  
16336259 A.N.Zelensky, and J.E.Gready (2005).
The C-type lectin-like domain superfamily.
  FEBS J, 272, 6179-6217.  
15894612 D.Garrity, M.E.Call, J.Feng, and K.W.Wucherpfennig (2005).
The activating NKG2D receptor assembles in the membrane with two signaling dimers into a hexameric structure.
  Proc Natl Acad Sci U S A, 102, 7641-7646.  
15821084 E.J.Adams, Y.H.Chien, and K.C.Garcia (2005).
Structure of a gammadelta T cell receptor in complex with the nonclassical MHC T22.
  Science, 308, 227-231.
PDB code: 1ypz
15939022 I.Ohki, T.Ishigaki, T.Oyama, S.Matsunaga, Q.Xie, M.Ohnishi-Kameyama, T.Murata, D.Tsuchiya, S.Machida, K.Morikawa, and S.Tate (2005).
Crystal structure of human lectin-like, oxidized low-density lipoprotein receptor 1 ligand binding domain and its ligand recognition mode to OxLDL.
  Structure, 13, 905-917.
PDB codes: 1yxj 1yxk
15850375 J.B.Ames, V.Vyas, J.D.Lusin, and R.Mariuzza (2005).
NMR structure of the natural killer cell receptor 2B4 (CD244): implications for ligand recognition.
  Biochemistry, 44, 6416-6423.
PDB code: 1z2k
15771571 L.L.Lanier (2005).
NK cell recognition.
  Annu Rev Immunol, 23, 225-274.  
15858601 L.Windsor, M.Puschendorf, R.Allcock, A.Scott, D.Sayer, R.Kucharzak, I.Gut, V.McCann, E.Davis, C.Witt, F.Christiansen, and P.Price (2005).
Does a central MHC gene in linkage disequilibrium with HLA-DRB1*0401 affect susceptibility to type 1 diabetes?
  Genes Immun, 6, 298-304.  
20476991 R.Biassoni, and N.Dimasi (2005).
Human natural killer cell receptor functions and their implication in diseases.
  Expert Rev Clin Immunol, 1, 405-417.  
16089503 R.Olson, K.E.Huey-Tubman, C.Dulac, and P.J.Bjorkman (2005).
Structure of a pheromone receptor-associated MHC molecule with an open and empty groove.
  PLoS Biol, 3, e257.
PDB code: 1zs8
15304008 M.Schroeder, H.A.Elsner, T.D.Kim, and R.Blasczyk (2004).
Eight novel MICB alleles, including a null allele, identified in gastric MALT lymphoma patients.
  Tissue Antigens, 64, 276-280.  
15131306 X.L.He, and K.C.Garcia (2004).
Structure of nerve growth factor complexed with the shared neurotrophin receptor p75.
  Science, 304, 870-875.
PDB code: 1sg1
12653967 A.M.Wong, R.J.Allcock, K.Y.Cheong, F.T.Christiansen, and P.Price (2003).
Alleles of the proximal promoter of BAT1, a putative anti-inflammatory gene adjacent to the TNF cluster, reduce transcription on a disease-associated MHC haplotype.
  Genes Cells, 8, 403-412.  
12802013 A.Sato, W.E.Mayer, P.Overath, and J.Klein (2003).
Genes encoding putative natural killer cell C-type lectin receptors in teleostean fishes.
  Proc Natl Acad Sci U S A, 100, 7779-7784.  
14670298 B.J.McFarland, and R.K.Strong (2003).
Thermodynamic analysis of degenerate recognition by the NKG2D immunoreceptor: not induced fit but rigid adaptation.
  Immunity, 19, 803-812.  
14670294 D.H.Margulies (2003).
Molecular interactions: stiff or floppy (or somewhere in between?).
  Immunity, 19, 772-774.  
12782717 I.H.Westgaard, E.Dissen, K.M.Torgersen, S.Lazetic, L.L.Lanier, J.H.Phillips, and S.Fossum (2003).
The lectin-like receptor KLRE1 inhibits natural killer cell cytotoxicity.
  J Exp Med, 197, 1551-1561.  
14563312 M.Gleimer, and P.Parham (2003).
Stress management: MHC class I and class I-like molecules as reporters of cellular stress.
  Immunity, 19, 469-477.  
12411439 R.K.Strong, M.A.Holmes, P.Li, L.Braun, N.Lee, and D.E.Geraghty (2003).
HLA-E allelic variants. Correlating differential expression, peptide affinities, crystal structures, and thermal stabilities.
  J Biol Chem, 278, 5082-5090.
PDB codes: 1kpr 1ktl
12471063 S.Radaev, and P.D.Sun (2003).
Structure and function of natural killer cell surface receptors.
  Annu Rev Biophys Biomol Struct, 32, 93.  
12668644 X.Saulquin, L.N.Gastinel, and E.Vivier (2003).
Crystal structure of the human natural killer cell activating receptor KIR2DS2 (CD158j).
  J Exp Med, 197, 933-938.
PDB code: 1m4k
12115588 C.Menier, B.Riteau, E.D.Carosella, and N.Rouas-Freiss (2002).
MICA triggering signal for NK cell tumor lysis is counteracted by HLA-G1-mediated inhibitory signal.
  Int J Cancer, 100, 63-70.  
11973127 E.Vivier, E.Tomasello, and P.Paul (2002).
Lymphocyte activation via NKG2D: towards a new paradigm in immune recognition?
  Curr Opin Immunol, 14, 306-311.  
12445274 F.E.McCann, K.Suhling, L.M.Carlin, K.Eleme, S.B.Taner, K.Yanagi, B.Vanherberghen, P.M.French, and D.M.Davis (2002).
Imaging immune surveillance by T cells and NK cells.
  Immunol Rev, 189, 179-192.  
12183162 K.L.McQueen, and P.Parham (2002).
Variable receptors controlling activation and inhibition of NK cells.
  Curr Opin Immunol, 14, 615-621.  
11861620 K.Natarajan, N.Dimasi, J.Wang, R.A.Mariuzza, and D.H.Margulies (2002).
Structure and function of natural killer cell receptors: multiple molecular solutions to self, nonself discrimination.
  Annu Rev Immunol, 20, 853-885.  
11864610 M.M.Mullen, K.M.Haan, R.Longnecker, and T.S.Jardetzky (2002).
Structure of the Epstein-Barr virus gp42 protein bound to the MHC class II receptor HLA-DR1.
  Mol Cell, 9, 375-385.
PDB code: 1kg0
12501157 R.L.Rich, and D.G.Myszka (2002).
Survey of the year 2001 commercial optical biosensor literature.
  J Mol Recognit, 15, 352-376.  
11880613 T.Spies (2002).
Induction of T cell alertness by bacterial colonization of intestinal epithelium.
  Proc Natl Acad Sci U S A, 99, 2584-2586.  
11830641 V.Tieng, C.Le Bouguénec, L.du Merle, P.Bertheau, P.Desreumaux, A.Janin, D.Charron, and A.Toubert (2002).
Binding of Escherichia coli adhesin AfaE to CD55 triggers cell-surface expression of the MHC class I-related molecule MICA.
  Proc Natl Acad Sci U S A, 99, 2977-2982.  
12392510 Y.S.Park, C.B.Sanjeevi, D.Robles, L.Yu, M.Rewers, P.A.Gottlieb, P.Fain, and G.S.Eisenbarth (2002).
Additional association of intra-MHC genes, MICA and D6S273, with Addison's disease.
  Tissue Antigens, 60, 155-163.  
11429322 H.A.Stephens (2001).
MICA and MICB genes: can the enigma of their polymorphism be resolved?
  Trends Immunol, 22, 378-385.  
11785767 H.Kogelberg, and T.Feizi (2001).
New structural insights into lectin-type proteins of the immune system.
  Curr Opin Struct Biol, 11, 635-643.  
11567627 J.Trowsdale (2001).
Genetic and functional relationships between MHC and NK receptor genes.
  Immunity, 15, 363-374.  
11754823 S.Radaev, B.Rostro, A.G.Brooks, M.Colonna, and P.D.Sun (2001).
Conformational plasticity revealed by the cocrystal structure of NKG2D and its class I MHC-like ligand ULBP3.
  Immunity, 15, 1039-1049.
PDB code: 1kcg
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.