title: Solution structure and dynamics of human hemoglobin in the carbonmonoxy form.
abstract: The solution structure of human adult carbonmonoxy hemoglobin (HbCO A) was refined using stereospecifically assigned methyl groups and residual dipolar couplings based on our previous nuclear magnetic resonance structure. The tertiary structures of individual chains were found to be very similar to the X-ray structures, while the quaternary structures in solution at low salt concentrations resembled the X-ray R structure more than the R2 structure. On the basis of chemical shift perturbation by inositol hexaphosphate (IHP) titration and docking, we identified five possible IHP binding sites in HbCO A. Amide-water proton exchange experiments demonstrated that αThr38 located in the α1β2 interface and several loop regions in both α- and β-chains were dynamic on the subsecond time scale. Side chain methyl dynamics revealed that methyl groups in the α1β2 interface were dynamic, but those in the α1β1 interface were quite rigid on the nanosecond to picosecond and millisecond to microsecond time scales. All the data strongly suggest a dynamic α1β2 interface that allows conformational changes among different forms (like T, R, and R2) easily in solution. Binding of IHP to HbCO A induced small structural and dynamic changes in the α1β2 interface and the regions around the hemes but did not increase the conformational entropy of HbCO A. The binding also caused conformational changes on the millisecond time scale, very likely arising from the relative motion of the α1β1 dimer with respect to the α2β2 dimer. Heterotropic effectors like IHP may change the oxygen affinity of Hb through modulating the relative motion of the two dimers and then further altering the structure of heme binding regions.
authors.affiliation: Department of Biological Sciences, National University of Singapore, 14 Science Drive 4, Singapore.
authors.forename: Jing-Song
authors.initials: JS
authors.lastname: Fan
authors.forename: Yu
authors.initials: Y
authors.lastname: Zheng
authors.forename: Wing-Yiu
authors.initials: WY
authors.lastname: Choy
authors.forename: Virgil
authors.initials: V
authors.lastname: Simplaceanu
authors.forename: Nancy T
authors.initials: NT
authors.lastname: Ho
authors.forename: Chien
authors.initials: C
authors.lastname: Ho
authors.forename: Daiwen
authors.initials: D
authors.lastname: Yang
mesh_terms: D000328:Adult; D002263:Carboxyhemoglobin / Q000737:chemistry* / Q000187:drug effects; D006418:Heme / Q000378:metabolism; D006441:Hemoglobin A / Q000737:chemistry*; D006801:Humans; D062105:Molecular Docking Simulation; D010833:Phytic Acid / Q000378:metabolism / Q000494:pharmacology; D011487:Protein Conformation; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D012996:Solutions
chemical_list: D012996:Solutions; D006418:Heme; D010833:Phytic Acid; D006441:Hemoglobin A; D002263:Carboxyhemoglobin
references.citation: Biophys J. 2008 Apr 1;94(7):2737-51
references.pmid: 18096633
references.citation: J Mol Biol. 2002 Aug 30;321(5):863-78
references.pmid: 12206767
references.citation: Biochemistry. 2006 Apr 25;45(16):5140-8
references.pmid: 16618103
references.citation: Biophys J. 2000 Aug;79(2):1146-54
references.pmid: 10920044
references.citation: J Comput Chem. 2009 Dec;30(16):2785-91
references.pmid: 19399780
references.citation: J Mol Graph. 1996 Feb;14(1):51-5, 29-32
references.pmid: 8744573
references.citation: J Mol Biol. 2009 Apr 24;388(1):1-10
references.pmid: 19281819
references.citation: J Mol Biol. 1998 Mar 13;276(5):939-54
references.pmid: 9566198
references.citation: J Mol Biol. 1996 Oct 25;263(2):369-82
references.pmid: 8913313
references.citation: Nature. 1974 May 3;249(452):34-6
references.pmid: 4364353
references.citation: FEBS Lett. 2005 Jan 31;579(3):627-32
references.pmid: 15670819
references.citation: Curr Opin Struct Biol. 2003 Dec;13(6):748-57
references.pmid: 14675554
references.citation: Nat Chem Biol. 2009 Nov;5(11):789-96
references.pmid: 19841628
references.citation: Proc Natl Acad Sci U S A. 2003 Jan 21;100(2):517-20
references.pmid: 12525687
references.citation: J Biol Chem. 1992 Aug 25;267(24):17248-56
references.pmid: 1512262
references.citation: J Mol Biol. 2006 Feb 24;356(3):790-801
references.pmid: 16403522
references.citation: Biochemistry. 2005 Jun 14;44(23):8347-59
references.pmid: 15938624
references.citation: Proc Natl Acad Sci U S A. 1994 Nov 8;91(23):11113-7
references.pmid: 7972019
references.citation: Nat Methods. 2006 Nov;3(11):931-7
references.pmid: 17060917
references.citation: Biochemistry. 1996 Jan 16;35(2):361-8
references.pmid: 8555205
references.citation: Protein Pept Lett. 2011 Apr;18(4):380-95
references.pmid: 21222636
references.citation: J Mol Biol. 2011 May 20;408(5):909-21
references.pmid: 21420976
references.citation: Eur J Biochem. 1981 Aug;118(1):95-104
references.pmid: 7285916
references.citation: Biochemistry. 2008 Apr 29;47(17):4907-15
references.pmid: 18376851
references.citation: J Biomol NMR. 1995 Nov;6(3):277-93
references.pmid: 8520220
references.citation: J Comput Chem. 2010 Jan 30;31(2):455-61
references.pmid: 19499576
references.citation: J Biomol NMR. 2007 May;38(1):79-88
references.pmid: 17464570
references.citation: Biophys J. 2005 Aug;89(2):1203-13
references.pmid: 15894633
references.citation: Nat Chem Biol. 2010 May;6(5):352-8
references.pmid: 20383153
references.citation: Proc Natl Acad Sci U S A. 2001 Mar 27;98(7):3773-7
references.pmid: 11259676
references.citation: J Biomol NMR. 1996 Dec;8(4):477-86
references.pmid: 9008363
references.citation: J Biol Chem. 2002 Sep 13;277(37):34508-20
references.pmid: 12107163
references.citation: Biochemistry. 1989 Nov 14;28(23):8972-9
references.pmid: 2690953
references.citation: Nature. 1970 Nov 21;228(5273):726-39
references.pmid: 5528785
references.citation: Nature. 2012 Aug 9;488(7410):236-40
references.pmid: 22801505
references.citation: Curr Opin Struct Biol. 2011 Feb;21(1):62-7
references.pmid: 21109422
references.citation: Eur J Biochem. 1981 Aug;118(1):85-94
references.pmid: 7285915
references.citation: J Biomol NMR. 1998 Feb;11(2):221-6
references.pmid: 9679296
references.citation: J Am Chem Soc. 2006 Apr 19;128(15):5073-81
references.pmid: 16608341
references.citation: J Magn Reson. 2003 Jan;160(1):65-73
references.pmid: 12565051
references.citation: Biochemistry. 2007 Jun 12;46(23):6795-803
references.pmid: 17497935
references.citation: J Mol Biol. 1965 May;12:88-118
references.pmid: 14343300
references.citation: Biochim Biophys Acta. 2008 Sep;1784(9):1146-58
references.pmid: 18519045
references.citation: Biochemistry. 1989 Sep 19;28(19):7510-6
references.pmid: 2692701
references.citation: Biochemistry. 2000 Dec 19;39(50):15353-64
references.pmid: 11112521