PDBsum entry 1k8i

Go to PDB code: 
protein ligands Protein-protein interface(s) links
Immune system PDB id
Protein chains
181 a.a. *
190 a.a. *
NAG ×2
* Residue conservation analysis
PDB id:
Name: Immune system
Title: Crystal structure of mouse h2-dm
Structure: Mhc class ii h2-m alpha chain. Chain: a. Engineered: yes. Mhc class ii h2-m beta 2 chain. Chain: b. Engineered: yes
Source: Mus musculus. House mouse. Organism_taxid: 10090. Gene: h2-dm. Expressed in: trichoplusia ni. Expression_system_taxid: 7111. Expression_system_cell_line: high-five.
Biol. unit: Dimer (from PQS)
3.10Å     R-factor:   0.205     R-free:   0.256
Authors: D.H.Fremont,F.Crawford,P.Marrack,W.Hendrickson,J.Kappler
Key ref:
D.H.Fremont et al. (1998). Crystal structure of mouse H2-M. Immunity, 9, 385-393. PubMed id: 9768758 DOI: 10.1016/S1074-7613(00)80621-4
24-Oct-01     Release date:   05-Dec-01    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P28078  (DMA_MOUSE) -  Class II histocompatibility antigen, M alpha chain
261 a.a.
181 a.a.*
Protein chain
Pfam   ArchSchema ?
Q31099  (Q31099_MOUSE) -  H2-M beta 2
261 a.a.
190 a.a.
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 2 residue positions (black crosses)

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     membrane   2 terms 
  Biological process     immune response   2 terms 


DOI no: 10.1016/S1074-7613(00)80621-4 Immunity 9:385-393 (1998)
PubMed id: 9768758  
Crystal structure of mouse H2-M.
D.H.Fremont, F.Crawford, P.Marrack, W.A.Hendrickson, J.Kappler.
H2-M (HLA-DM in humans) resides in an acidic endosomal compartment, where it facilitates the loading of antigenic peptides into the peptide-binding groove of class II MHC. The crystal structure of a soluble form of H2-M has been solved to 3.1 A resolution, revealing a heterodimer with structural similarities to the MHC family of proteins. In contrast to its antigen-presenting cousins, the membrane distal alpha helices of H2-M pack closely together, occluding most of the binding groove except for a single large pocket near the center. The structure of H2-M has several unique features that may play a role in its function as a molecular chaperone and peptide exchange factor.
  Selected figure(s)  
Figure 4.
Figure 4. Surface Features of H2-M(A) A molecular surface image (GRASP; [38]) of H2-M color-coded by sequence variation among H2-M αβ[2], H2-M αβ[1], and HLA-DM (Figure 2). The view is from the top of the α-helical regions. Residues that are invariant among all three molecules are gray. Those that differ between H2-M αβ[2] and HLA-DM but not between H2-M αβ[2] and H-2M αβ[1] are green. Those that differ between H2-M αβ[2] and H−2M αβ[1] but not between H2-M αβ[2] and HLA-DR are light yellow. Finally, those that differ among all three molecules are bright yellow. Individual domains are labeled and special features are demarcated. Notable in this view is the P4′ pocket, which is lined with conserved residues but which is somewhat variable around its edges. The region around the classic P1 pocket is remarkably conserved however. Also indicated is a hydrophobic seam located between the α1 domain h2 helix and β1 domain h1 helix near the classic P6 and P9 pockets. At the edge of this region is a potential N-linked glycosylation site found in H2M β[1] but not β[2].(B) Side view of H2-M with the β2 domain in front and the α helices tipped forward. The electrostatic surface was calculated using standard conventions ([38]). The surface is colored according to the local electrostatic potential, with negative in red and positive in blue. The highly acidic character of the surface is evident. Several conserved surface features are labeled. A solvent accessible hydrophobic ledge is formed primarily by the s4 strand of the H2-M β1 domain and its connection to the h1 α helix. This ledge lies adjacent to a cluster of three exposed cysteines. This area is flanked by a number of acidic residues (β7, β30, β36, and β46). Another acidic cluster is formed by adjacent acidic residues on the loop between the α1 s2 and s3 strands (α35-α37) and one at the end of the α2 D strand (α151). These residues form part of a contact region between the α1 and α2 domains. Underlining indicates acidic residues that are conserved in H2-M αβ2, H2-Mαβ1, and HLA-DM, but not in class II MHC.
Figure 5.
Figure 5. Expression and Characterization of Soluble H2-M(A) The strategy for cloning the extracellular domains of H2-M in a baculovirus transfer vector is shown. The oligonucleotide primers containing the restriction enzyme recognition sites shown (left and right arrows) were used in a PCR to synthesize sequence encoding the extracellular domains of H2-M. The fragments were then cloned in frame with sequence encoding αβTCR leader peptides for expression in baculovirus. See the Results and Discussion and Experimental Procedures for details.(B) Purified soluble H2-M was analyzed by SDS-PAGE, isoelectric focusing (IEF), and native PAGE using the Phast system (Pharmacia). 0.5–1.0 μg of H2-M were loaded in each lane. SDS-PAGE molecular weight and native PAGE standards were from Pharmacia. IEF standards were from Sigma.
  The above figures are reprinted by permission from Cell Press: Immunity (1998, 9, 385-393) copyright 1998.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
23222639 A.I.Guce, S.E.Mortimer, T.Yoon, C.A.Painter, W.Jiang, E.D.Mellins, and L.J.Stern (2013).
HLA-DO acts as a substrate mimic to inhibit HLA-DM by a competitive mechanism.
  Nat Struct Mol Biol, 20, 90-98.
PDB code: 4i0p
23288359 L.K.Denzin, and P.Cresswell (2013).
Sibling rivalry: competition between MHC class II family members inhibits immunity.
  Nat Struct Mol Biol, 20, 7.  
21131964 A.K.Anders, M.J.Call, M.S.Schulze, K.D.Fowler, D.A.Schubert, N.P.Seth, E.J.Sundberg, and K.W.Wucherpfennig (2011).
HLA-DM captures partially empty HLA-DR molecules for catalyzed removal of peptide.
  Nat Immunol, 12, 54-61.  
20382987 H.Walden (2010).
Selenium incorporation using recombinant techniques.
  Acta Crystallogr D Biol Crystallogr, 66, 352-357.  
19538060 D.Loose, and C.Van de Wiele (2009).
The immune system and cancer.
  Cancer Biother Radiopharm, 24, 369-376.  
19019088 F.Deshaies, D.A.Diallo, J.S.Fortin, H.M.O'Rourke, A.M.Pezeshki, A.Bellemare-Pelletier, N.Raby, N.Bédard, A.Brunet, L.K.Denzin, and J.Thibodeau (2009).
Evidence for a human leucocyte antigen-DM-induced structural change in human leucocyte antigen-DObeta.
  Immunology, 127, 408-417.  
19119025 G.Dong, P.A.Wearsch, D.R.Peaper, P.Cresswell, and K.M.Reinisch (2009).
Insights into MHC class I peptide loading from the structure of the tapasin-ERp57 thiol oxidoreductase heterodimer.
  Immunity, 30, 21-32.
PDB code: 3f8u
18767126 R.Yaneva, S.Springer, and M.Zacharias (2009).
Flexibility of the MHC class II peptide binding cleft in the bound, partially filled, and empty states: A molecular dynamics simulation study.
  Biopolymers, 91, 14-27.  
18261958 S.Sadegh-Nasseri, M.Chen, K.Narayan, and M.Bouvier (2008).
The convergent roles of tapasin and HLA-DM in antigen presentation.
  Trends Immunol, 29, 141-147.  
17660253 C.N.Cronin, K.B.Lim, and J.Rogers (2007).
Production of selenomethionyl-derivatized proteins in baculovirus-infected insect cells.
  Protein Sci, 16, 2023-2029.  
17525157 G.M.Grotenbreg, M.J.Nicholson, K.D.Fowler, K.Wilbuer, L.Octavio, M.Yang, A.K.Chakraborty, H.L.Ploegh, and K.W.Wucherpfennig (2007).
Empty class II major histocompatibility complex created by peptide photolysis establishes the role of DM in peptide association.
  J Biol Chem, 282, 21425-21436.  
16682499 C.A.Lazarski, F.A.Chaves, and A.J.Sant (2006).
The impact of DM on MHC class II-restricted antigen presentation can be altered by manipulation of MHC-peptide kinetic stability.
  J Exp Med, 203, 1319-1328.  
15883386 H.J.Kim, D.Guo, and D.B.Sant'Angelo (2005).
Coevolution of TCR-MHC interactions: conserved MHC tertiary structure is not sufficient for interactions with the TCR.
  Proc Natl Acad Sci U S A, 102, 7263-7267.  
16181343 L.K.Denzin, J.L.Fallas, M.Prendes, and W.Yi (2005).
Right place, right time, right peptide: DO keeps DM focused.
  Immunol Rev, 207, 279-292.  
16181341 R.Busch, C.H.Rinderknecht, S.Roh, A.W.Lee, J.J.Harding, T.Burster, T.M.Hornell, and E.D.Mellins (2005).
Achieving stability through editing and chaperoning: regulation of MHC class II peptide binding and expression.
  Immunol Rev, 207, 242-260.  
16181344 S.B.Lovitch, and E.R.Unanue (2005).
Conformational isomers of a peptide-class II major histocompatibility complex.
  Immunol Rev, 207, 293-313.  
15245391 S.I.Jarvi, C.L.Tarr, C.E.McIntosh, C.T.Atkinson, and R.C.Fleischer (2004).
Natural selection of the major histocompatibility complex (Mhc) in Hawaiian honeycreepers (Drepanidinae).
  Mol Ecol, 13, 2157-2168.  
15084275 Z.Pu, S.B.Lovitch, E.K.Bikoff, and E.R.Unanue (2004).
T cells distinguish MHC-peptide complexes formed in separate vesicles and edited by H2-DM.
  Immunity, 20, 467-476.  
11857638 B.J.McFarland, and C.Beeson (2002).
Binding interactions between peptides and proteins of the class II major histocompatibility complex.
  Med Res Rev, 22, 168-203.  
12119342 E.Stratikos, L.Mosyak, D.M.Zaller, and D.C.Wiley (2002).
Identification of the lateral interaction surfaces of human histocompatibility leukocyte antigen (HLA)-DM with HLA-DR1 by formation of tethered complexes that present enhanced HLA-DM catalysis.
  J Exp Med, 196, 173-183.  
12419245 J.M.Alexander, C.A.Nelson, V.van Berkel, E.K.Lau, J.M.Studts, T.J.Brett, S.H.Speck, T.M.Handel, H.W.Virgin, and D.H.Fremont (2002).
Structural basis of chemokine sequestration by a herpesvirus decoy receptor.
  Cell, 111, 343-356.
PDB codes: 1mkf 1ml0
11790529 P.Brocke, N.Garbi, F.Momburg, and G.J.Hämmerling (2002).
HLA-DM, HLA-DO and tapasin: functional similarities and differences.
  Curr Opin Immunol, 14, 22-29.  
11606721 J.A.Zarutskie, R.Busch, Z.Zavala-Ruiz, M.Rushe, E.D.Mellins, and L.J.Stern (2001).
The kinetic basis of peptide exchange catalysis by HLA-DM.
  Proc Natl Acad Sci U S A, 98, 12450-12455.  
10636922 A.K.Sato, J.A.Zarutskie, M.M.Rushe, A.Lomakin, S.K.Natarajan, S.Sadegh-Nasseri, G.B.Benedek, and L.J.Stern (2000).
Determinants of the peptide-induced conformational change in the human class II major histocompatibility complex protein HLA-DR1.
  J Biol Chem, 275, 2165-2173.  
10837054 C.Alfonso, and L.Karlsson (2000).
Nonclassical MHC class II molecules.
  Annu Rev Immunol, 18, 113-142.  
11120767 C.L.Chou, and S.Sadegh-Nasseri (2000).
HLA-DM recognizes the flexible conformation of major histocompatibility complex class II.
  J Exp Med, 192, 1697-1706.  
10748231 M.van Ham, M.van Lith, B.Lillemeier, E.Tjin, U.Grüneberg, D.Rahman, L.Pastoors, K.van Meijgaarden, C.Roucard, J.Trowsdale, T.Ottenhoff, D.Pappin, and J.Neefjes (2000).
Modulation of the major histocompatibility complex class II-associated peptide repertoire by human histocompatibility leukocyte antigen (HLA)-DO.
  J Exp Med, 191, 1127-1136.  
10679402 R.Busch, R.C.Doebele, N.S.Patil, A.Pashine, and E.D.Mellins (2000).
Accessory molecules for MHC class II peptide loading.
  Curr Opin Immunol, 12, 99.  
11070170 R.C.Doebele, R.Busch, H.M.Scott, A.Pashine, and E.D.Mellins (2000).
Determination of the HLA-DM interaction site on HLA-DR molecules.
  Immunity, 13, 517-527.  
10716924 S.O.Arndt, A.B.Vogt, S.Markovic-Plese, R.Martin, G.Moldenhauer, A.Wölpl, Y.Sun, D.Schadendorf, G.J.Hämmerling, and H.Kropshofer (2000).
Functional HLA-DM on the surface of B cells and immature dendritic cells.
  EMBO J, 19, 1241-1251.  
10888612 V.van Berkel, J.Barrett, H.L.Tiffany, D.H.Fremont, P.M.Murphy, G.McFadden, S.H.Speck, and I.V.Virgin HW (2000).
Identification of a gammaherpesvirus selective chemokine binding protein that inhibits chemokine action.
  J Virol, 74, 6741-6747.  
11027433 W.Walter, K.Lingnau, E.Schmitt, M.Loos, and M.J.Maeurer (2000).
MHC class II antigen presentation pathway in murine tumours: tumour evasion from immunosurveillance?
  Br J Cancer, 83, 1192-1201.  
10625593 A.B.Vogt, S.O.Arndt, G.J.Hämmerling, and H.Kropshofer (1999).
Quality control of MHC class II associated peptides by HLA-DM/H2-M.
  Semin Immunol, 11, 391-403.  
10631951 C.Alfonso, M.Liljedahl, O.Winqvist, C.D.Surh, P.A.Peterson, W.P.Fung-Leung, and L.Karlsson (1999).
The role of H2-O and HLA-DO in major histocompatibility complex class II-restricted antigen processing and presentation.
  Immunol Rev, 172, 255-266.  
10631952 H.Kropshofer, G.J.Hämmerling, and A.B.Vogt (1999).
The impact of the non-classical MHC proteins HLA-DM and HLA-DO on loading of MHC class II molecules.
  Immunol Rev, 172, 267-278.  
10231540 J.A.Zarutskie, A.K.Sato, M.M.Rushe, I.C.Chan, A.Lomakin, G.B.Benedek, and L.J.Stern (1999).
A conformational change in the human major histocompatibility complex protein HLA-DR1 induced by peptide binding.
  Biochemistry, 38, 5878-5887.  
10574801 J.J.Bellizzi, J.Widom, C.W.Kemp, and J.Clardy (1999).
Producing selenomethionine-labeled proteins with a baculovirus expression vector system.
  Structure, 7, R263-R267.  
10607669 K.Maenaka, and E.Y.Jones (1999).
MHC superfamily structure and the immune system.
  Curr Opin Struct Biol, 9, 745-753.  
10084794 P.Cresswell, and J.Howard (1999).
Antigen recognition.
  Curr Opin Immunol, 11, 61-63.  
10741860 P.E.Jensen, D.A.Weber, W.P.Thayer, X.Chen, and C.T.Dao (1999).
HLA-DM and the MHC class II antigen presentation pathway.
  Immunol Res, 20, 195-205.  
10508247 P.W.Bryant, P.Roos, H.L.Ploegh, and A.J.Sant (1999).
Deviant trafficking of I-Ad mutant molecules is reflected in their peptide binding properties.
  Eur J Immunol, 29, 2729-2739.  
10631947 R.Wubbolts, and J.Neefjes (1999).
Intracellular transport and peptide loading of MHC class II molecules: regulation by chaperones and motors.
  Immunol Rev, 172, 189-208.  
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.