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Electrostatic Potential on HLA-DPB1*1701 and HLA-DPB1*0401: Implications for Putative Mechanism of Chronic Beryllium Dis

Electrostatic Potential on HLA-DPB1*1701 and HLA-DPB1*0401: Implications for Putative Mechanism of Chronic Beryllium Disease. James A. Snyder, Ainsley Weston, Sally S. Tinkle and Eugene Demchuk. Health Effects Laboratory Division, National Institute for Occupational Safety and Health,

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Electrostatic Potential on HLA-DPB1*1701 and HLA-DPB1*0401: Implications for Putative Mechanism of Chronic Beryllium Dis

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  1. Electrostatic Potential onHLA-DPB1*1701 and HLA-DPB1*0401:Implications for Putative Mechanism of Chronic Beryllium Disease James A. Snyder, Ainsley Weston, Sally S. Tinkle and Eugene Demchuk Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, WV

  2. Objective to understand the physical-chemical reasons for beryllium toxicity in Chronic Beryllium Disease (CBD)

  3. What makes Be toxic? Periodic Table

  4. The Test Hypothesis Be2+ binds to HLA-DP and changes the specificity of molecular recognition Goal: To identify and test the Be2+ binding mode

  5. Experimental Evidence • Amicosante, M., Sanarico, N. Berretta, F., Arroyo, J., Lombardi, G., Lechler, R., Colizzi, V. and Saltini, C. Beryllium Binding to HLA-DP Molecule Carrying the Marker of Susceptibility to Berylliosis Glutamate 69.Human Immunology, 62, 686-693 (2001) • Fontenot, A.P., Torres, M., Marshall, W.H., Newman, L.S. and Kotzin, B.L. Beryllium Presentation to CD4+ T Cells Underlies Disease-Susceptibility HLA-DP Alleles in Chronic Beryllium Disease. Proc. Natl. Acad. Sci. USA,97, 12717-12722 (2000)

  6. a b cell membrane MHC class II

  7. Crystal Structure of Human Class II MHC Proteinsin the Protein Data Bank (PDB) HLA-DR1 • 1AQD HLA-DR1 (DRA, DRB1 0101) Human MHC Class II complexed with endogenous peptide • 1DLH HLA-DR1 (DRA, DRB1 0101) Human Class II histocompatibility protein (extracellular domain) • 1FYT HLA-DR1, DRB1 0101 • 1HQR DRA*0101 + DRB5*0101 • 1KG0 the Epstein-Barr virus Gp42 Protein bound to the MHC Class II HLA-DR1 • 1SEB complex of the Human MHC Class II Glycoprotein HLA-DR1 and the bacterial superantigen SEB HLA-DR2 • 1BX2 HLA-DR2 (DRA*0101, DRB1*1501) complexed with a peptide from Human myelin basic protein • 1FV1 immunodominant peptide from myelin basic protein in different registers by two HLA-DR2 alleles HLA-DR3 • 1A6A clip bound to HLA-DR3 HLA-DR4 • 1D5M HLA-DR4 complexed with peptide and SEB • 1D5X HLA-DR4 complexed with dipeptide mimetic and SEB • 1D5Z HLA-DR4 complexed with peptidomimetic and SEB • 1D6E HLA-DR4 complex with peptidomimetic and SEB • 1J8H HLA-DR1, DRA + HLA-DR4, DRB1*0401 • 2SEB HLA-DR4 complexed with a peptide from Human collagen II HLA-DQ8 • 1JK8 Human insulin peptide-HLA-DQ8 complex HLA-DM • 1HDM histocompatibility antigen HLA-DM

  8. Sequence Alignment of HLA-DPB1*1701 with  chain of HLA-DR2 (PDB: 1FV1B) 10 20 30 40 *1701RATPENYVHQLRQECYAFNGTQR - -FLERYIYNREEFVRFDS 1FV1GDTRPRFLQQDKYECHFFNGTERVRFLHRDIYNQEEDLRFDS 10 20 30 40 50 60 70 80 *1701DVGE FRAVTELGRPDEDYWNSQKDILEEERAVPDRMCRHN 1FV1DVGEYRAVTELGRPDAEYWNSQKDFLEDRRAAVDTYCRHN 50 60 70 80 90 100 110 120 *1701YELDEAVTLQRRVQPKVNVSPSKKGPLQHHNLLVCHVTDF 1FV1YGVGESFTVQRRVEPKVTVYPARTQTLQHHNLLVCSVNGF 90 100 110 120 130 140 150 160 *1701YPGSIQVRWFLNGQEETAGVVSTNLIRNGDWTFQ ILVMLE 1FV1YPGSIEVRWFRNSQEEKAGVVSTGLIQNGDWTFQTLVMLE 130 140 150 160 170 180 190 200 *1701MTPQQGDVY ICQVEHTSLDSPVTVEWKAQSDSAQSKTLTG 1FV1TVP RSGEVYTCQVEHPSVTSPLTVEWRA 170 180 190

  9. Molecular Dynamics…

  10. Total Deviation of a-carbon atom coordinates relative to starting (crystallographic) positions at 1 Pico-second intervals

  11. Total Chargeon HLA-DP proteins Be2+ DR Template Protein: -14 a/b HLA-DPA1*01031/B1*0401: -17/-3 HLA-DPA1*01031/B1*1701: -17/-9

  12. CBD Susceptibility Odds and the Charge on b-chain of HLA-DP HLA-DPB1 Odds Charge *1701 -9 *0601 -9 *0901, *1001 -9, -9 *1901 -8 *0201 -7 *0401 -3

  13. Sequence Alignment of HLA-DPB1*1701 with HLA-DPB1*0401 1 40 *1701 RATPENYVHQLRQECYAFNG TQRFLERYIYNREEFVRFDS *0401 RATPENY LFQGRQECYAFNG TQRFLERYIYNREEFARFDS 41 -1-1-2 80 *1701 DVGEFRAVTE LGRPDEDYWNSQKDILEEERAVPDRMCRHN *0401 DVGEFRAVTELGRPAAEYWNSQKDILEEKRAVPDRMCRHN 81 -1-1 120 *1701 YELDEA VTLQRRVQPKVNVSPSKKGPLQHH NLLVCHVTDF *0401 YELGGPMTLQRRVQPRVNVSPSKKGPLQHH NLLVCHVTDF 121 160 *1701 YPGSIQVRWF LNGQEETAGV VSTNLIRNGD WTFQILVMLE *0401 YPGSIQVRWF LNGQEETAGV VSTNLIRNGD WTFQILVMLE 161 188 *1701 MTPQQGDVY ICQVEHTSLDS PVTVEWKA *0401 MTPQQGDVYTCQVEHTSLDS PVTVEWKA

  14. Class II MHC antigen-binding Pocket <- b-chain <- a-chain

  15. S Poisson-Boltzmann Equation

  16. Finite Difference PB Methods • using divergence theorem:

  17. Electrostatic Potential Surface Map HLA-DPA1*01031/B1*0401 (model)

  18. HLA-DPA1*01031/B1*1701 (model) Electrostatic Potential Surface Map

  19. *1701 MEP Movie

  20. *0401 MEP Movie

  21. 1701 MEP Movie

  22. Conclusion Our results are consistent with the hypothesis that glutamic acid at position 69 of the b-chain of HLA-DP may be a determinant of susceptibility to Chronic Beryllium Disease

  23. People James A. Snyder Eugene Demchuk Ainsley Weston genetics Sally S. Tinkle immunology computational studies Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, WV

  24. Future Goal: To model interactions of Be2+ with HLA-DP proteins

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