Subject: Summary for Examples for Main Chain Flexible Docking

From: "Prof. Luhua LAI" <[email-masked]>
Date: Thu, 20 Nov 1997 14:15:44 -0800 (PST)

Dear CCLers:

Several days ago, I posted the following question:  

We are studying main chain flexibility in protein-protein or protein-ligand
docking. We would like to find some examples where protein main chain
conformation changes significantly when binds with other molecule. Could
someone give me a few examples? 

Thanks for all who responded to the question. The following is a summary for
all the answers. 
 
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 German Sastre                       URL: http://www.ri.ac.uk/DFRL/G.Sastre
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  it could be of interest bearing in mind what happens in some organic bases
  called 'proton sponges':

  some of them have this 'basic group':      

    			R#	 R*
			 \      /
			R-N    N-R
			  |    |       well, sorry about the picture but,
			  C----C       believe it or not, the 'square' is
			  |    |       a naftalene molecule
			  |    |
			  ------

  Now the important thing: in the basic form (as depicted) the repulsion between
  the lone pairs makes the dihedral R#-N-N-R* to have a certain value (the
  dihedral changes through nearly free rotation around the N-C bonds). In the 
  acid form (after getting a H+) that repulsion becomes attraction (now there
  is only one lone pair and the proton), and the dihedral changes accordingly.

  May be you can find a similar effect in your protein-ligand interactions.
  In your case protein makes the role of sponge and ligand plays the role
  of the proton.

  good luck!
  German
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 German Sastre                       URL: http://www.ri.ac.uk/DFRL/G.Sastre
 Instituto de Tecnologia Quimica                 e-mail: [email-masked]
 Universidad Politecnica de Valencia               Phone: +34 (9)6-387-7803
 Camino de Vera s/n; 46071 Valencia (Spain)        Fax:   +34 (9)6-387-7809
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                                            oo0 0oo
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>From [email-masked]  Wed Nov 12 16:11:19 1997
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The best example for a main-chain rearrangement upon binding IMHO is the
case of Fab50.1, a HIV-1 neutralizing antibody (cf.R.L. Stanfield and I. A.
Wilson, Trends in Biotechnology, July 1994 (vol 12), 275-9)). Here a
main-chain RMSD of 5.3 Angstrom, corresponding to a scissor-like movement
of V_l with respect to V_h is observed.

In the case of protein-small molecule binding, I somehow have the
thrombin-hirudin case in my mind (you might have to check this,
though...). 

Looking forward to hearing from you. Best regards,

	Lutz Ehrlich

---------------------
Lutz Ehrlich

Structural Biology
EMBL
Meyerhofstr. 1
D-69012 Heidelberg
Germany

email: [email-masked]
web  : http://www.embl-heidelberg.de/~ehrlich
phone: +49-6221-387-140
fax  : +49-6221-387-517
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>From [email-masked]  Wed Nov 12 21:09:43 1997
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Dr. Lai:  The "flap" region of HIV protease undergoes significant
rigidification upon binding of a substrate or ligand.  In this
99-mer protein, I refer to region 45-55, also called the "flap"
region.  There is a crystal structure of an unliganded form, where
the flap is held in place by a crystal contact.  But it is obvious
that the flap has multiple conformations in solution.  In the
liganded form, there are probably 30 crystal structures in the
PDB which show the flap in nearly identical "locked-down" 
conformation.

Kent Stewart
Department of Structural Biology
Abbott Laboratories
Chicago, IL
United States of America
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>From [email-masked]  Wed Nov 12 23:05:33 1997
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The nuclear hormone receptor ligand binding domain is a good example.

See Wurtz et al., Nature Structural Biology vol. 3, 1996, pp 87-94
and Renaud et al., Nature vol. 378, 1994, pp. 681-689.

Good luck,

Donald Doyle
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 Donald F. Doyle, Ph.D.				[email-masked]
 Howard Hughes Medical Institute		Phone: (214) 648-6787
 UT Southwestern Medical Center			Fax:   (214) 648-5095
 5323 Harry Hines Blvd. Y4.320
 Dallas, TX 75235-9050
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>From [email-masked]  Thu Nov 13 01:24:53 1997
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The ligand binding domain of Nuclear Receptors (NRs) is an interesting case to
study. The crystal structure of unliganded and liganded ligand binding domains
are available (These is the so called steroid/thyroid hormone superfamily).
Ligand binding induces a important transconformation the active complex is then
able to modulate the transcription of target genes. Relevant references are the
following :
- Bourguet, W.; Ruff, M.; Chambon, P.; Gronemeyer, H.; Moras, D. Crystal
structure of the ligand-binding domain of the human nuclear receptor RXR-alpha.
Nature 1995, 375, 377-382.

- Renaud, J. P.; Rochel, N.; Ruff, M.; Vivat, V.; Chambon, P.; Gronemeyer, H.;
Moras, D. Crystal structure of the RAR-gamma ligand-binding domain bound to
all-trans retinoic acid. Nature 1995, 378, 681-689.

- Wagner, R. L.; Apriletti, J. W.; McGrath, M. E.; West, B. L.; Baxter, J. D.;
Fletterick, R. J. A structural role for hormone in the thyroid hormone
receptor. Nature 1995, 378, 690-697.

- Wurtz, J. M.; Bourguet, W.; Renaud, J. P.; Vivat, V.; Chambon, P.; Moras, D.;
Gronemeyer, H. A canonical structure for the ligand-binding domain of nuclear
receptors [published erratum appears in Nat Struct Biol 1996 Feb; 3(2):206].
Nat. Struct. Biol. 1996, 3, 87-94.

Friendly,

-- 

				WURTZ Jean-Marie

________________________________________________________________________
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Laboratoire de Biologie Structurale	Phone :  (33) 3 88 65 35 29
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>From [email-masked]  Thu Nov 13 09:32:53 1997
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Luhua,

HIV protease is a good example. The binding site are made of a pair
of catalytic triad of Gly, Asp, and Thr. and two beta sheet loops.
When it is free of ligand binding, the two loops are open. They are
moved about 4 Angstroms Upon binding to a inhibitor, to cover up
the binding cavity. You can find the crystal structures of both
in free and bounded form. I do not quite remember the file names.
let me know if you have difficulty finding it at pdb site.

Another one would be antibody binding to antigen. I know much less
in this case. Just a suggestion.

Best regards!
-- 
Willie Cui			voice: 201-512-0486
MicroSimulations		fax:   201-512-0489
478 Green Mountain Road		email: [email-masked]
Mahwah, NJ 07430		URL:   http://www.microsimulations.com
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>From [email-masked]  Fri Nov 14 13:02:40 1997
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According to X-ray analysis, the structure of CDK2 shows much
movement of main chain when cycinA binds to it.
See 1HCK and 1FIN in PDB.

＊＊＊＊＊＊＊＊＊＊＊＊＊＊＊＊＊＊＊＊
Toshiharu Iwama
Molecular Modeling Group
Banyu Pharmaceutical Co.,LTD.
Okubo 3, Tsukuba 300-26, JAPAN
E-mail     [email-masked]

Tel  +81-298-77-2000
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------------------------------------------  
   Luhua Lai
   Institute of Physical Chemistry
   & Department of Chemistry          
   Peking University
   Beijing 100871
   CHINA
   Phone: 86-10-62751490
   Fax:   86-10-62751725
   E-mail: [email-masked]
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